Pain

In-office procedures are increasingly emphasized as a way to reduce referrals, avoid treatment delay, and increase practice revenue. Local analgesia is administered before many in-office procedures such as biopsies, toenail removal, and laceration repair. Skin procedures are performed most commonly; nearly three-quarters (74%) of family physicians (FPs) provided these services in 2018.¹ Administration of local anesthetic is often the most feared and uncomfortable step in the entire process.²

Knowledge of strategies to reduce pain associated with anesthetic administration can make a huge difference in the patient experience. This article explores evidence-based techniques for administering a local anesthetic with minimal patient discomfort.

4 factors influence the painof local anesthetic administration

Pain is perceived during the administration of local anesthetic because of the insertion of the needle and the increased pressure from the injection of fluid. The needle causes sharp, pricking “first pain” via large diameter, myelinated A-delta fibers, and the fluid induces unmyelinated C-fiber activation via tissue distention resulting in dull, diffuse “second pain.”

Four factors influence the experience of pain during administration of local anesthetic: the pharmacologic properties of the anesthetic itself, the equipment used, the environment, and the injection technique. Optimizing all 4 factors limits patient discomfort.

Pharmacologic agents: Lidocaine is often the agent of choice

Local anesthetics differ in maximal dosing, onset of action, and duration of effect (TABLE³). Given its ubiquity in clinics and hospitals, 1% lidocaine is often the agent of choice. Onset of effect occurs within minutes and lasts up to 2 hours. Alternative agents, such as bupivacaine or ropivacaine, may be considered to prolong the anesthetic effect; however, limited evidence exists to support their use in office-based procedures. Additionally, bupivacaine and ropivacaine may be associated with greater pain on injection and parasthesias lasting longer than the duration of pain control.^4-6 In practice, maximal dosing is most important in the pediatric population, given the smaller size of the patients and their increased susceptibility to toxicity.

Calculating the maximum recommended dose. To calculate the maximum recommended dose of local anesthetic, you need to know the concentration of the anesthetic, the maximum allowable dose (mg/kg), and the weight of the patient.^7,8 The concentration of the local anesthetic is converted from percentage to weight per unit volume (eg, 1% = 10 mg/mL; 0.5% = 5 mg/mL). Multiply the patient's weight (kg) by the maximum dose of local anesthetic (mg/kg) and divide by the concentration of the local anesthetic (mg/mL) to get the maximum recommended dose in milliliters. Walsh et al⁹ described a simplified formula to calculate the maximum allowable volume of local anesthetics in milliliters:

(maximum allowable dose in mg/kg) × (weight in kg) × (1 divided by the concentration of anesthetic).

For delivery of lidocaine with epinephrine in a 50-lb (22.7-kg) child, the calculation would be (7 mg/kg) × (22.7 kg) × (1 divided by 10 mg/mL) = 15.9 mL.

Continue to: The advantages (and misconceptions) of epinephrine

The advantage of adding epinephrine is that it prolongs the effect of the anesthesia and it decreases bleeding. Epinephrine is commonly available as a premixed solution with lidocaine or bupivacaine at a concentration of 1:100,000 and is generally differentiated from “plain” local anesthetic by a red label and cap. Although maximum vasoconstriction may occur as long as 30 minutes after injection,¹⁰ adequate vasoconstriction is achieved in 7 to 10 minutes for excision of skin lesions.¹¹

Traditional teaching recommends against using epinephrine in the “fingers, toes, penis, ears, or nose” because of potential arterial spasm, ischemia, and gangrene distal to the injection site.¹² These concerns were based on experiences with procaine and cocaine mixed with epinephrine. Studies suffered from multiple confounders, including tourniquets and nonstandardized epinephrine concentrations.^13-15

Add epinephrine to the anesthetic solution to prolong anesthesia and decrease bleeding.

No association of distal ischemia with epinephrine use was identified in a recent Cochrane Review or in another multicenter prospective study.^16,17 Phentolamine, a non-selective alpha-adrenergic receptor antagonist and vasodilator, can be administered to reverse vasoconstriction following inadvertent administration of high-dose epinephrine (1:1000) via anaphylaxis autoinjector kits.

Dosing of phentolamine is 1 mL of 1 mg/mL solution delivered subcutaneously to the affected area; reversal decreases the duration of vasoconstriction from 320 minutes to approximately 85 minutes.¹⁸ As always, when applying literature to clinical practice, one must keep in mind the risks and benefits of any intervention. As such, in patients with pre-existing vascular disease, vaso-occlusive or vasospastic disease, or compromised perfusion due to trauma, one must weigh the benefits of the hemostatic effect against potential ischemia of already susceptible tissues. In such instances, omitting epinephrine from the solution is reasonable.

The benefits of sodium bicarbonate

The acidity of the solution contributes to the level of pain associated with administration of local anesthesia. Previously opened containers become more acidic.¹⁹ Addition of 8.4% sodium bicarbonate, at a ratio of 1 mL per 10 mL of 1% lidocaine with 1:100,000 epinephrine, neutralizes the pH to 7.4.¹⁹ A Cochrane Review showed that correction of pH to physiologic levels results in a significant reduction in pain.²⁰

Continue to: This solution can be...

This solution can be easily prepared, as standard syringes hold an additional milliliter (ie, 10-mL syringes hold 11 mL) and, thus, can accommodate the additional volume of bicarbonate.²¹

Warming the solution helps, too

Warming the solution to body temperature prior to injection decreases pain on injection.²² This may be done in a variety of ways depending on available in-office equipment. Water baths, incubators, fluid warmers, heating pads, or specific syringe warmers may be used. Multiple studies have shown improvement in patient satisfaction with warming.²³ Moreover, warming and buffering solution provide a synergistic effect on pain reduction.²³

Equipment: Size matters

Smaller diameter needles. Reducing the outer diameter of the needle used for injection improves pain by reducing activation of nociceptors.^24-26 Reduced inner diameter restricts injection speed, which further reduces pain.²⁵ We recommend 27- to 30-gauge needles for subcutaneous injection and 25- to 27-gauge needles for intra-articular or tendon sheath injections.

Appropriate syringe size. Filling a syringe to capacity results in maximal deployment of the plunger. This requires greater handspan, which can lead to fatigue and loss of control during injection.^26,27 Using a syringe filled to approximately half its capacity results in improved dexterity. We recommend 10-mL syringes with 5 mL to 6 mL of local anesthetic for small procedures and 20-mL syringes filled with 10 mL to 12 mL for larger procedures.

Topical local anesthetics may be used either as an adjunct to decrease pain during injection or as the primary anesthetic.²⁸ A variety of agents are available for clinical use, including eutectic mixture of local anesthetics (EMLA), lidocaine-epinephrine-tetracaine (LET), lidocaine, benzocaine, and tetracaine. FPs should be familiar with their different pharmacokinetic profiles.

Continue to: EMLA is a mixture of...

EMLA is a mixture of 25 mg/mL of lidocaine and 25 mg/mL of prilocaine. It is indicated for topical anesthesia on intact, nonmucosal, uninjured skin (maximal dose 20 g/200 cm² of surface area). It is applied in a thick layer and covered with an occlusive dressing (eg, Tegaderm) to enhance dermal penetration. The depth of penetration increases with application time and may reach a maximum depth of 3 mm and 5 mm following 60-minute and 120-minute application times, respectively.²⁸ Duration of effect is 60 to 120 minutes.

LET, which is a mixture of 4% lidocaine, 0.1% epinephrine, and 0.5% tetracaine, may be used on nonintact, nonmucosal surfaces. Typically, 1 mL to 5 mL of gel is applied directly to the target area and is followed by application of direct pressure for 15 to 30 minutes. LET is not effective on intact skin and is contraindicated in children < 2 years of age.²⁸

Cooling sprays or ice. Topical skin refrigerants, or vapocoolants (eg, ethyl chloride spray), offer an option for short-term local anesthesia that is noninvasive and quick acting. Ethyl chloride is a gaseous substance that extracts heat as it evaporates from the skin, resulting in a transient local conduction block. Skin refrigerants are an option to consider for short procedures such as intra-articular injections, venipuncture, or skin tag excision, or as an adjunct prior to local anesthetic delivery.^29-32 Research has shown that topical ethyl chloride spray also possesses antiseptic properties.^29,33

Environment: Make a few simple changes

Direct observation of needle penetration is associated with increased pain; advising patients to avert their gaze will mitigate the perception of pain.³⁴ Additionally, research has shown that creating a low-anxiety environment improves patient-reported outcomes in both children and adults.³⁵ Music or audiovisual or multimedia aids, for example, decrease pain and anxiety, particularly among children, and can be readily accessed with smart devices.^36-39

Warming and buffering solution provide a synergistic effect on pain reduction.

We also recommend avoiding terms such as “pinch,” “bee sting,” or “stick” in order to reduce patient anxiety. Instead, we use language such as, “This is the medicine that will numb the area so you will be comfortable during the procedure.”⁴⁰

Continue to: Injection technique

Site of needle entry. Prior to injecting local anesthesia, assess the area where the procedure is planned (FIGURE 1). The initial injection site should be proximal along the path of innervation. If regional nerves are anesthetized proximally and infiltration of local anesthesia proceeds distally, the initial puncture will be painful; however, further injections will be through anesthetized skin. Additionally, consider and avoid regional vascular anatomy.^41,42

Counter-stimulation. Applying firm pressure, massaging, or stroking the site prior to or during the injection decreases pain.^43,44 This technique may be performed by firmly pinching the area of planned injection between the thumb and index fingers, inserting the needle into the pinched skin, and maintaining pressure on the area until the anesthetic effect is achieved.

Angle of needle insertion. Perpendicular entry of the needle into the skin appears to reduce injection site pain (FIGURE 1). Anecdotal reports are supported by a randomized, controlled crossover trial that demonstrated significantly reduced pain with perpendicular injection compared to delivery at 45°.⁴⁵

Depth of injection. Subcutaneous needle placement is associated with significantly less pain than injection into superficial dermis.^2,46 Dermal wheals cause distention of the dermis, increased intradermal pressure, and greater activation of pain afferents in comparison to injection in the subcutaneous space.⁴⁶ One important exception is the shave biopsy in which dermal distention is, in fact, desirable to ensure adequate specimen collection.

Other methods of pain reduction should still be employed. In the setting of traumatic wounds when a laceration is present, injection into the subcutaneous fat through the wound is easy and associated with less pain than injection through intact skin.⁴⁷

Continue to: Speed of injection

Speed of injection. Rapid injection of anesthesia is associated with worse injection site pain and decreased patient satisfaction.^48-50 Slowing the rate of injection causes less rapid distention of the dermis and subcutaneous space, resulting in decreased pain afferent activation and increased time for nerve blockade. Its importance is underscored by a prospective, randomized trial that compared rate of administration with buffering of local anesthetics and demonstrated that slow administration impacted patient-perceived pain more than buffering solution.⁵¹

Needle stabilization. Following perpendicular entry of the needle into the area of planned infiltration, deliver 0.5 mL of local anesthetic into the subcutaneous space without movement of the needle tip.⁵² With a stabilized needle tip, pain associated with initial needle entry is no longer perceived within 15 to 30 seconds.

Any reinsertion of the needle should be through previously anesthetized skin.

It is paramount to stabilize both the syringe and the area of infiltration to prevent patient movement from causing iatrogenic injury or the need for multiple needlesticks. This can be accomplished by maintaining the dominant hand in a position to inject (ie, thumb on the plunger).

Needle reinsertion. Once subcutaneous swelling of local anesthesia is obtained, the needle may be slowly advanced, maintaining a palpable subcutaneous wavefront of local anesthesia ahead of the needle tip as it moves proximally to distally.^2,52 Any reinsertion of the needle should be through previously anesthetized skin; this blockade is assessed by the presence of palpable tumescence and blanching (from the epinephrine effect).⁵³

An example of the application of these injection pearls is demonstrated in the ­administration of a digital nerve block in FIGURE 2.^54,55 With the use of the techniques outlined here, the patient ideally experiences only the initial needle entry and is comfortable for the remainder of the procedure.

PHOTO COURTESY OF BRENT DEGEORGE, MD, PhD, AND ROBERTO MARTINEZ, MD, THE UNIVERSITY OF VIRGINIA DEPARTMENT OF PLASTIC SURGERY

CORRESPONDENCE
Katharine C. DeGeorge, MD, MS, Department of Family Medicine, University of Virginia, 1215 Lee Street, Charlottesville, VA, 22903; [email protected].

In-office procedures are increasingly emphasized as a way to reduce referrals, avoid treatment delay, and increase practice revenue. Local analgesia is administered before many in-office procedures such as biopsies, toenail removal, and laceration repair. Skin procedures are performed most commonly; nearly three-quarters (74%) of family physicians (FPs) provided these services in 2018.¹ Administration of local anesthetic is often the most feared and uncomfortable step in the entire process.²

Knowledge of strategies to reduce pain associated with anesthetic administration can make a huge difference in the patient experience. This article explores evidence-based techniques for administering a local anesthetic with minimal patient discomfort.

4 factors influence the painof local anesthetic administration

Pain is perceived during the administration of local anesthetic because of the insertion of the needle and the increased pressure from the injection of fluid. The needle causes sharp, pricking “first pain” via large diameter, myelinated A-delta fibers, and the fluid induces unmyelinated C-fiber activation via tissue distention resulting in dull, diffuse “second pain.”

Four factors influence the experience of pain during administration of local anesthetic: the pharmacologic properties of the anesthetic itself, the equipment used, the environment, and the injection technique. Optimizing all 4 factors limits patient discomfort.

Pharmacologic agents: Lidocaine is often the agent of choice

Local anesthetics differ in maximal dosing, onset of action, and duration of effect (TABLE³). Given its ubiquity in clinics and hospitals, 1% lidocaine is often the agent of choice. Onset of effect occurs within minutes and lasts up to 2 hours. Alternative agents, such as bupivacaine or ropivacaine, may be considered to prolong the anesthetic effect; however, limited evidence exists to support their use in office-based procedures. Additionally, bupivacaine and ropivacaine may be associated with greater pain on injection and parasthesias lasting longer than the duration of pain control.^4-6 In practice, maximal dosing is most important in the pediatric population, given the smaller size of the patients and their increased susceptibility to toxicity.

Calculating the maximum recommended dose. To calculate the maximum recommended dose of local anesthetic, you need to know the concentration of the anesthetic, the maximum allowable dose (mg/kg), and the weight of the patient.^7,8 The concentration of the local anesthetic is converted from percentage to weight per unit volume (eg, 1% = 10 mg/mL; 0.5% = 5 mg/mL). Multiply the patient's weight (kg) by the maximum dose of local anesthetic (mg/kg) and divide by the concentration of the local anesthetic (mg/mL) to get the maximum recommended dose in milliliters. Walsh et al⁹ described a simplified formula to calculate the maximum allowable volume of local anesthetics in milliliters:

(maximum allowable dose in mg/kg) × (weight in kg) × (1 divided by the concentration of anesthetic).

For delivery of lidocaine with epinephrine in a 50-lb (22.7-kg) child, the calculation would be (7 mg/kg) × (22.7 kg) × (1 divided by 10 mg/mL) = 15.9 mL.

Continue to: The advantages (and misconceptions) of epinephrine

The advantage of adding epinephrine is that it prolongs the effect of the anesthesia and it decreases bleeding. Epinephrine is commonly available as a premixed solution with lidocaine or bupivacaine at a concentration of 1:100,000 and is generally differentiated from “plain” local anesthetic by a red label and cap. Although maximum vasoconstriction may occur as long as 30 minutes after injection,¹⁰ adequate vasoconstriction is achieved in 7 to 10 minutes for excision of skin lesions.¹¹

Traditional teaching recommends against using epinephrine in the “fingers, toes, penis, ears, or nose” because of potential arterial spasm, ischemia, and gangrene distal to the injection site.¹² These concerns were based on experiences with procaine and cocaine mixed with epinephrine. Studies suffered from multiple confounders, including tourniquets and nonstandardized epinephrine concentrations.^13-15

Add epinephrine to the anesthetic solution to prolong anesthesia and decrease bleeding.

No association of distal ischemia with epinephrine use was identified in a recent Cochrane Review or in another multicenter prospective study.^16,17 Phentolamine, a non-selective alpha-adrenergic receptor antagonist and vasodilator, can be administered to reverse vasoconstriction following inadvertent administration of high-dose epinephrine (1:1000) via anaphylaxis autoinjector kits.

Dosing of phentolamine is 1 mL of 1 mg/mL solution delivered subcutaneously to the affected area; reversal decreases the duration of vasoconstriction from 320 minutes to approximately 85 minutes.¹⁸ As always, when applying literature to clinical practice, one must keep in mind the risks and benefits of any intervention. As such, in patients with pre-existing vascular disease, vaso-occlusive or vasospastic disease, or compromised perfusion due to trauma, one must weigh the benefits of the hemostatic effect against potential ischemia of already susceptible tissues. In such instances, omitting epinephrine from the solution is reasonable.

The benefits of sodium bicarbonate

The acidity of the solution contributes to the level of pain associated with administration of local anesthesia. Previously opened containers become more acidic.¹⁹ Addition of 8.4% sodium bicarbonate, at a ratio of 1 mL per 10 mL of 1% lidocaine with 1:100,000 epinephrine, neutralizes the pH to 7.4.¹⁹ A Cochrane Review showed that correction of pH to physiologic levels results in a significant reduction in pain.²⁰

Continue to: This solution can be...

This solution can be easily prepared, as standard syringes hold an additional milliliter (ie, 10-mL syringes hold 11 mL) and, thus, can accommodate the additional volume of bicarbonate.²¹

Warming the solution helps, too

Warming the solution to body temperature prior to injection decreases pain on injection.²² This may be done in a variety of ways depending on available in-office equipment. Water baths, incubators, fluid warmers, heating pads, or specific syringe warmers may be used. Multiple studies have shown improvement in patient satisfaction with warming.²³ Moreover, warming and buffering solution provide a synergistic effect on pain reduction.²³

Equipment: Size matters

Smaller diameter needles. Reducing the outer diameter of the needle used for injection improves pain by reducing activation of nociceptors.^24-26 Reduced inner diameter restricts injection speed, which further reduces pain.²⁵ We recommend 27- to 30-gauge needles for subcutaneous injection and 25- to 27-gauge needles for intra-articular or tendon sheath injections.

Appropriate syringe size. Filling a syringe to capacity results in maximal deployment of the plunger. This requires greater handspan, which can lead to fatigue and loss of control during injection.^26,27 Using a syringe filled to approximately half its capacity results in improved dexterity. We recommend 10-mL syringes with 5 mL to 6 mL of local anesthetic for small procedures and 20-mL syringes filled with 10 mL to 12 mL for larger procedures.

Topical local anesthetics may be used either as an adjunct to decrease pain during injection or as the primary anesthetic.²⁸ A variety of agents are available for clinical use, including eutectic mixture of local anesthetics (EMLA), lidocaine-epinephrine-tetracaine (LET), lidocaine, benzocaine, and tetracaine. FPs should be familiar with their different pharmacokinetic profiles.

Continue to: EMLA is a mixture of...

EMLA is a mixture of 25 mg/mL of lidocaine and 25 mg/mL of prilocaine. It is indicated for topical anesthesia on intact, nonmucosal, uninjured skin (maximal dose 20 g/200 cm² of surface area). It is applied in a thick layer and covered with an occlusive dressing (eg, Tegaderm) to enhance dermal penetration. The depth of penetration increases with application time and may reach a maximum depth of 3 mm and 5 mm following 60-minute and 120-minute application times, respectively.²⁸ Duration of effect is 60 to 120 minutes.

LET, which is a mixture of 4% lidocaine, 0.1% epinephrine, and 0.5% tetracaine, may be used on nonintact, nonmucosal surfaces. Typically, 1 mL to 5 mL of gel is applied directly to the target area and is followed by application of direct pressure for 15 to 30 minutes. LET is not effective on intact skin and is contraindicated in children < 2 years of age.²⁸

Cooling sprays or ice. Topical skin refrigerants, or vapocoolants (eg, ethyl chloride spray), offer an option for short-term local anesthesia that is noninvasive and quick acting. Ethyl chloride is a gaseous substance that extracts heat as it evaporates from the skin, resulting in a transient local conduction block. Skin refrigerants are an option to consider for short procedures such as intra-articular injections, venipuncture, or skin tag excision, or as an adjunct prior to local anesthetic delivery.^29-32 Research has shown that topical ethyl chloride spray also possesses antiseptic properties.^29,33

Environment: Make a few simple changes

Direct observation of needle penetration is associated with increased pain; advising patients to avert their gaze will mitigate the perception of pain.³⁴ Additionally, research has shown that creating a low-anxiety environment improves patient-reported outcomes in both children and adults.³⁵ Music or audiovisual or multimedia aids, for example, decrease pain and anxiety, particularly among children, and can be readily accessed with smart devices.^36-39

Warming and buffering solution provide a synergistic effect on pain reduction.

We also recommend avoiding terms such as “pinch,” “bee sting,” or “stick” in order to reduce patient anxiety. Instead, we use language such as, “This is the medicine that will numb the area so you will be comfortable during the procedure.”⁴⁰

Continue to: Injection technique

Site of needle entry. Prior to injecting local anesthesia, assess the area where the procedure is planned (FIGURE 1). The initial injection site should be proximal along the path of innervation. If regional nerves are anesthetized proximally and infiltration of local anesthesia proceeds distally, the initial puncture will be painful; however, further injections will be through anesthetized skin. Additionally, consider and avoid regional vascular anatomy.^41,42

Counter-stimulation. Applying firm pressure, massaging, or stroking the site prior to or during the injection decreases pain.^43,44 This technique may be performed by firmly pinching the area of planned injection between the thumb and index fingers, inserting the needle into the pinched skin, and maintaining pressure on the area until the anesthetic effect is achieved.

Angle of needle insertion. Perpendicular entry of the needle into the skin appears to reduce injection site pain (FIGURE 1). Anecdotal reports are supported by a randomized, controlled crossover trial that demonstrated significantly reduced pain with perpendicular injection compared to delivery at 45°.⁴⁵

Depth of injection. Subcutaneous needle placement is associated with significantly less pain than injection into superficial dermis.^2,46 Dermal wheals cause distention of the dermis, increased intradermal pressure, and greater activation of pain afferents in comparison to injection in the subcutaneous space.⁴⁶ One important exception is the shave biopsy in which dermal distention is, in fact, desirable to ensure adequate specimen collection.

Other methods of pain reduction should still be employed. In the setting of traumatic wounds when a laceration is present, injection into the subcutaneous fat through the wound is easy and associated with less pain than injection through intact skin.⁴⁷

Continue to: Speed of injection

Speed of injection. Rapid injection of anesthesia is associated with worse injection site pain and decreased patient satisfaction.^48-50 Slowing the rate of injection causes less rapid distention of the dermis and subcutaneous space, resulting in decreased pain afferent activation and increased time for nerve blockade. Its importance is underscored by a prospective, randomized trial that compared rate of administration with buffering of local anesthetics and demonstrated that slow administration impacted patient-perceived pain more than buffering solution.⁵¹

Needle stabilization. Following perpendicular entry of the needle into the area of planned infiltration, deliver 0.5 mL of local anesthetic into the subcutaneous space without movement of the needle tip.⁵² With a stabilized needle tip, pain associated with initial needle entry is no longer perceived within 15 to 30 seconds.

Any reinsertion of the needle should be through previously anesthetized skin.

It is paramount to stabilize both the syringe and the area of infiltration to prevent patient movement from causing iatrogenic injury or the need for multiple needlesticks. This can be accomplished by maintaining the dominant hand in a position to inject (ie, thumb on the plunger).

Needle reinsertion. Once subcutaneous swelling of local anesthesia is obtained, the needle may be slowly advanced, maintaining a palpable subcutaneous wavefront of local anesthesia ahead of the needle tip as it moves proximally to distally.^2,52 Any reinsertion of the needle should be through previously anesthetized skin; this blockade is assessed by the presence of palpable tumescence and blanching (from the epinephrine effect).⁵³

An example of the application of these injection pearls is demonstrated in the ­administration of a digital nerve block in FIGURE 2.^54,55 With the use of the techniques outlined here, the patient ideally experiences only the initial needle entry and is comfortable for the remainder of the procedure.

PHOTO COURTESY OF BRENT DEGEORGE, MD, PhD, AND ROBERTO MARTINEZ, MD, THE UNIVERSITY OF VIRGINIA DEPARTMENT OF PLASTIC SURGERY

CORRESPONDENCE
Katharine C. DeGeorge, MD, MS, Department of Family Medicine, University of Virginia, 1215 Lee Street, Charlottesville, VA, 22903; [email protected].

In-office procedures are increasingly emphasized as a way to reduce referrals, avoid treatment delay, and increase practice revenue. Local analgesia is administered before many in-office procedures such as biopsies, toenail removal, and laceration repair. Skin procedures are performed most commonly; nearly three-quarters (74%) of family physicians (FPs) provided these services in 2018.¹ Administration of local anesthetic is often the most feared and uncomfortable step in the entire process.²

Knowledge of strategies to reduce pain associated with anesthetic administration can make a huge difference in the patient experience. This article explores evidence-based techniques for administering a local anesthetic with minimal patient discomfort.

4 factors influence the painof local anesthetic administration

Pain is perceived during the administration of local anesthetic because of the insertion of the needle and the increased pressure from the injection of fluid. The needle causes sharp, pricking “first pain” via large diameter, myelinated A-delta fibers, and the fluid induces unmyelinated C-fiber activation via tissue distention resulting in dull, diffuse “second pain.”

Four factors influence the experience of pain during administration of local anesthetic: the pharmacologic properties of the anesthetic itself, the equipment used, the environment, and the injection technique. Optimizing all 4 factors limits patient discomfort.

Pharmacologic agents: Lidocaine is often the agent of choice

Local anesthetics differ in maximal dosing, onset of action, and duration of effect (TABLE³). Given its ubiquity in clinics and hospitals, 1% lidocaine is often the agent of choice. Onset of effect occurs within minutes and lasts up to 2 hours. Alternative agents, such as bupivacaine or ropivacaine, may be considered to prolong the anesthetic effect; however, limited evidence exists to support their use in office-based procedures. Additionally, bupivacaine and ropivacaine may be associated with greater pain on injection and parasthesias lasting longer than the duration of pain control.^4-6 In practice, maximal dosing is most important in the pediatric population, given the smaller size of the patients and their increased susceptibility to toxicity.

Calculating the maximum recommended dose. To calculate the maximum recommended dose of local anesthetic, you need to know the concentration of the anesthetic, the maximum allowable dose (mg/kg), and the weight of the patient.^7,8 The concentration of the local anesthetic is converted from percentage to weight per unit volume (eg, 1% = 10 mg/mL; 0.5% = 5 mg/mL). Multiply the patient's weight (kg) by the maximum dose of local anesthetic (mg/kg) and divide by the concentration of the local anesthetic (mg/mL) to get the maximum recommended dose in milliliters. Walsh et al⁹ described a simplified formula to calculate the maximum allowable volume of local anesthetics in milliliters:

(maximum allowable dose in mg/kg) × (weight in kg) × (1 divided by the concentration of anesthetic).

For delivery of lidocaine with epinephrine in a 50-lb (22.7-kg) child, the calculation would be (7 mg/kg) × (22.7 kg) × (1 divided by 10 mg/mL) = 15.9 mL.

Continue to: The advantages (and misconceptions) of epinephrine

The advantage of adding epinephrine is that it prolongs the effect of the anesthesia and it decreases bleeding. Epinephrine is commonly available as a premixed solution with lidocaine or bupivacaine at a concentration of 1:100,000 and is generally differentiated from “plain” local anesthetic by a red label and cap. Although maximum vasoconstriction may occur as long as 30 minutes after injection,¹⁰ adequate vasoconstriction is achieved in 7 to 10 minutes for excision of skin lesions.¹¹

Traditional teaching recommends against using epinephrine in the “fingers, toes, penis, ears, or nose” because of potential arterial spasm, ischemia, and gangrene distal to the injection site.¹² These concerns were based on experiences with procaine and cocaine mixed with epinephrine. Studies suffered from multiple confounders, including tourniquets and nonstandardized epinephrine concentrations.^13-15

Add epinephrine to the anesthetic solution to prolong anesthesia and decrease bleeding.

No association of distal ischemia with epinephrine use was identified in a recent Cochrane Review or in another multicenter prospective study.^16,17 Phentolamine, a non-selective alpha-adrenergic receptor antagonist and vasodilator, can be administered to reverse vasoconstriction following inadvertent administration of high-dose epinephrine (1:1000) via anaphylaxis autoinjector kits.

Dosing of phentolamine is 1 mL of 1 mg/mL solution delivered subcutaneously to the affected area; reversal decreases the duration of vasoconstriction from 320 minutes to approximately 85 minutes.¹⁸ As always, when applying literature to clinical practice, one must keep in mind the risks and benefits of any intervention. As such, in patients with pre-existing vascular disease, vaso-occlusive or vasospastic disease, or compromised perfusion due to trauma, one must weigh the benefits of the hemostatic effect against potential ischemia of already susceptible tissues. In such instances, omitting epinephrine from the solution is reasonable.

The benefits of sodium bicarbonate

The acidity of the solution contributes to the level of pain associated with administration of local anesthesia. Previously opened containers become more acidic.¹⁹ Addition of 8.4% sodium bicarbonate, at a ratio of 1 mL per 10 mL of 1% lidocaine with 1:100,000 epinephrine, neutralizes the pH to 7.4.¹⁹ A Cochrane Review showed that correction of pH to physiologic levels results in a significant reduction in pain.²⁰

Continue to: This solution can be...

This solution can be easily prepared, as standard syringes hold an additional milliliter (ie, 10-mL syringes hold 11 mL) and, thus, can accommodate the additional volume of bicarbonate.²¹

Warming the solution helps, too

Warming the solution to body temperature prior to injection decreases pain on injection.²² This may be done in a variety of ways depending on available in-office equipment. Water baths, incubators, fluid warmers, heating pads, or specific syringe warmers may be used. Multiple studies have shown improvement in patient satisfaction with warming.²³ Moreover, warming and buffering solution provide a synergistic effect on pain reduction.²³

Equipment: Size matters

Smaller diameter needles. Reducing the outer diameter of the needle used for injection improves pain by reducing activation of nociceptors.^24-26 Reduced inner diameter restricts injection speed, which further reduces pain.²⁵ We recommend 27- to 30-gauge needles for subcutaneous injection and 25- to 27-gauge needles for intra-articular or tendon sheath injections.

Appropriate syringe size. Filling a syringe to capacity results in maximal deployment of the plunger. This requires greater handspan, which can lead to fatigue and loss of control during injection.^26,27 Using a syringe filled to approximately half its capacity results in improved dexterity. We recommend 10-mL syringes with 5 mL to 6 mL of local anesthetic for small procedures and 20-mL syringes filled with 10 mL to 12 mL for larger procedures.

Topical local anesthetics may be used either as an adjunct to decrease pain during injection or as the primary anesthetic.²⁸ A variety of agents are available for clinical use, including eutectic mixture of local anesthetics (EMLA), lidocaine-epinephrine-tetracaine (LET), lidocaine, benzocaine, and tetracaine. FPs should be familiar with their different pharmacokinetic profiles.

Continue to: EMLA is a mixture of...

EMLA is a mixture of 25 mg/mL of lidocaine and 25 mg/mL of prilocaine. It is indicated for topical anesthesia on intact, nonmucosal, uninjured skin (maximal dose 20 g/200 cm² of surface area). It is applied in a thick layer and covered with an occlusive dressing (eg, Tegaderm) to enhance dermal penetration. The depth of penetration increases with application time and may reach a maximum depth of 3 mm and 5 mm following 60-minute and 120-minute application times, respectively.²⁸ Duration of effect is 60 to 120 minutes.

LET, which is a mixture of 4% lidocaine, 0.1% epinephrine, and 0.5% tetracaine, may be used on nonintact, nonmucosal surfaces. Typically, 1 mL to 5 mL of gel is applied directly to the target area and is followed by application of direct pressure for 15 to 30 minutes. LET is not effective on intact skin and is contraindicated in children < 2 years of age.²⁸

Cooling sprays or ice. Topical skin refrigerants, or vapocoolants (eg, ethyl chloride spray), offer an option for short-term local anesthesia that is noninvasive and quick acting. Ethyl chloride is a gaseous substance that extracts heat as it evaporates from the skin, resulting in a transient local conduction block. Skin refrigerants are an option to consider for short procedures such as intra-articular injections, venipuncture, or skin tag excision, or as an adjunct prior to local anesthetic delivery.^29-32 Research has shown that topical ethyl chloride spray also possesses antiseptic properties.^29,33

Environment: Make a few simple changes

Direct observation of needle penetration is associated with increased pain; advising patients to avert their gaze will mitigate the perception of pain.³⁴ Additionally, research has shown that creating a low-anxiety environment improves patient-reported outcomes in both children and adults.³⁵ Music or audiovisual or multimedia aids, for example, decrease pain and anxiety, particularly among children, and can be readily accessed with smart devices.^36-39

Warming and buffering solution provide a synergistic effect on pain reduction.

We also recommend avoiding terms such as “pinch,” “bee sting,” or “stick” in order to reduce patient anxiety. Instead, we use language such as, “This is the medicine that will numb the area so you will be comfortable during the procedure.”⁴⁰

Continue to: Injection technique

Site of needle entry. Prior to injecting local anesthesia, assess the area where the procedure is planned (FIGURE 1). The initial injection site should be proximal along the path of innervation. If regional nerves are anesthetized proximally and infiltration of local anesthesia proceeds distally, the initial puncture will be painful; however, further injections will be through anesthetized skin. Additionally, consider and avoid regional vascular anatomy.^41,42

Counter-stimulation. Applying firm pressure, massaging, or stroking the site prior to or during the injection decreases pain.^43,44 This technique may be performed by firmly pinching the area of planned injection between the thumb and index fingers, inserting the needle into the pinched skin, and maintaining pressure on the area until the anesthetic effect is achieved.

Angle of needle insertion. Perpendicular entry of the needle into the skin appears to reduce injection site pain (FIGURE 1). Anecdotal reports are supported by a randomized, controlled crossover trial that demonstrated significantly reduced pain with perpendicular injection compared to delivery at 45°.⁴⁵

Depth of injection. Subcutaneous needle placement is associated with significantly less pain than injection into superficial dermis.^2,46 Dermal wheals cause distention of the dermis, increased intradermal pressure, and greater activation of pain afferents in comparison to injection in the subcutaneous space.⁴⁶ One important exception is the shave biopsy in which dermal distention is, in fact, desirable to ensure adequate specimen collection.

Other methods of pain reduction should still be employed. In the setting of traumatic wounds when a laceration is present, injection into the subcutaneous fat through the wound is easy and associated with less pain than injection through intact skin.⁴⁷

Continue to: Speed of injection

Speed of injection. Rapid injection of anesthesia is associated with worse injection site pain and decreased patient satisfaction.^48-50 Slowing the rate of injection causes less rapid distention of the dermis and subcutaneous space, resulting in decreased pain afferent activation and increased time for nerve blockade. Its importance is underscored by a prospective, randomized trial that compared rate of administration with buffering of local anesthetics and demonstrated that slow administration impacted patient-perceived pain more than buffering solution.⁵¹

Needle stabilization. Following perpendicular entry of the needle into the area of planned infiltration, deliver 0.5 mL of local anesthetic into the subcutaneous space without movement of the needle tip.⁵² With a stabilized needle tip, pain associated with initial needle entry is no longer perceived within 15 to 30 seconds.

Any reinsertion of the needle should be through previously anesthetized skin.

It is paramount to stabilize both the syringe and the area of infiltration to prevent patient movement from causing iatrogenic injury or the need for multiple needlesticks. This can be accomplished by maintaining the dominant hand in a position to inject (ie, thumb on the plunger).

Needle reinsertion. Once subcutaneous swelling of local anesthesia is obtained, the needle may be slowly advanced, maintaining a palpable subcutaneous wavefront of local anesthesia ahead of the needle tip as it moves proximally to distally.^2,52 Any reinsertion of the needle should be through previously anesthetized skin; this blockade is assessed by the presence of palpable tumescence and blanching (from the epinephrine effect).⁵³

An example of the application of these injection pearls is demonstrated in the ­administration of a digital nerve block in FIGURE 2.^54,55 With the use of the techniques outlined here, the patient ideally experiences only the initial needle entry and is comfortable for the remainder of the procedure.

PHOTO COURTESY OF BRENT DEGEORGE, MD, PhD, AND ROBERTO MARTINEZ, MD, THE UNIVERSITY OF VIRGINIA DEPARTMENT OF PLASTIC SURGERY

CORRESPONDENCE
Katharine C. DeGeorge, MD, MS, Department of Family Medicine, University of Virginia, 1215 Lee Street, Charlottesville, VA, 22903; [email protected].

STOWE, VT. – A large and growing number of medications is available for the acute treatment of migraine. Effective acute treatment enables patients to re-engage in their work and other daily activities, as well as reducing the likelihood that their disease will progress from episodic to chronic migraine. Considering appropriate routes of delivery, assessing efficacy and tolerability, and communicating well with the patient are essential components in the acute treatment of migraine, according to Barbara L. Nye, MD, assistant professor of neurology at the Geisel School of Medicine at Dartmouth, Hanover, N.H.. Dr. Nye discussed the acute treatment of migraine at the annual meeting of the Headache Cooperative of New England.

Choosing an initial treatment

Nonspecific medications are perhaps the first treatments to consider for a patient with acute migraine. This class includes NSAIDs such as naproxen sodium, piroxicam, diclofenac, celecoxib, and indomethacin. Emerging data indicate that some NSAIDs are associated with an increased risk of stroke, which is an important consideration as the population ages, said Dr. Nye. Other nonspecific options are neuroleptics such as prochlorperazine, metoclopramide, promethazine, and chlorpromazine. Many neuroleptics have sedative effects, however, so they do not necessarily help a patient return to function. Nevertheless, these drugs can be good rescue medications, said Dr. Nye.

Triptans are effective in the acute treatment of migraine, and seven drugs in this class are available. Most, such as rizatriptan, almotriptan, eletriptan, naratriptan, and frovatriptan, are available only as tablets. Other routes of delivery are available, however. Sumatriptan, for example, is available in injectable and intranasal formulations, and zolmitriptan is available as an orally dissolving tablet.

Another option to consider is dihydroergotamine (DHE), which has long been used for migraine. The injectable formulation of DHE can be cumbersome because it requires the patients with a headache to open a vial, draw the medication into a filter needle, and inject themselves, said Dr. Nye. “The nasal sprays that are available right now aren’t as effective as we’d like them to be,” she added. But overall, DHE is effective. Associated adverse events include flushing, nausea, and diarrhea.

Lasmiditan received approval from the Food and Drug Administration for the acute treatment of migraine in October 2019. Compared with placebo, the drug increases the likelihood of pain freedom and freedom from the most bothersome symptom at 2 hours. Driving tests indicated that patients were impaired for about 8 hours after treatment, and lasmiditan is a Schedule V drug. It is available in doses of 50 mg/day, 100 mg/day, and 200 mg/day.

The class of drugs known as the “gepants” provides further options. The most recently approved therapy in this class, which targets calcitonin gene–related peptide, is ubrogepant. Because the drug is metabolized through the CYP3A4 system, they are not appropriate for patients who use strong CYP3A4 inhibitors. The most common side effects are nausea, hypersensitivity reaction, and somnolence.

Neuromodulation can provide effective treatment without provoking side effects, said Dr. Nye. Options include transcutaneous supraorbital stimulation, single-pulse transcutaneous magnetic stimulation, noninvasive vagal nerve stimulation, and remote nonpainful stimulation.

If a patient presents during an acute attack, neurologists could consider using a nerve block. The latter may administer occipital nerve blocks, trigger point injections, auriculotemporal nerve blocks, and supraorbital and supratrochlear nerve blocks. This treatment can bring immediate relief, which is gratifying for patients and neurologists. But no consensus about which medications to use or how to administer them has been established. Neurologists most often use a combination of bupivacaine and lidocaine. Another possibility is a sphenopalatine ganglion nerve block, which requires treatment to be inserted through the nose. This treatment can be delivered in the office using the Sphenocath device or the Allevio device. Another device, the Tx360, is intended to enable patient self-administration.
 

Addressing treatment failure

If a patient returns and reports that the current treatment is ineffective, the neurologist must reevaluate the therapy. A helpful way to conduct this reassessment is to administer the Migraine Treatment Optimization Questionnaire (MTOQ), which was developed by Lipton et al., to the patient. Neurologists ask whether the patient can function normally 2 hours after treatment or whether the medication is, for example, causing a side effect that makes this outcome less likely. Other questions for the patient are whether the headache pain disappears within 2 hours and whether the medication provides consistent relief. Finally, the neurologist can ask whether the patient is comfortable taking the medication. A score lower than 2 on the MTOQ indicates that the acute treatment should be changed, said Dr. Nye.

Gastroparesis is common during migraine attacks. It is inadvisable to give an oral medication to a patient who vomits within 20 minutes of attack onset, said Dr. Nye. “It’s a little less intuitive for those people who are nauseous immediately to think that that oral tablet is probably going to sit in their stomach and not get absorbed in the intestines as intended.” Nasal sprays, injectable medicines, and oral dissolving tablets are appropriate options for patients with gastroparesis.
 

Treating migraine during pregnancy

Special consideration must be given to treatment when the patient is pregnant. Decreased headache frequency is common in pregnancy, but not universal. Occipital nerve blocks are a good option for prevention and acute management in pregnant patients. They may be administered every 2 weeks. Sphenopalatine ganglion nerve block is another option, and it can be administered several times per week. Data “suggest that stacking the injections 2 or 3 days per week for up to 6 weeks can eliminate headaches for up to 6 months,” said Dr. Nye.

Tylenol is appropriate for acute headache in pregnant patients, “but we do warn about medication overuse headache and limiting its use.” Ondansetron and promethazine are acceptable treatments for nausea. Although ondansetron has less central activity than promethazine, and thus does not reduce the headache, it lessens nausea, said Dr. Nye.

Triptan exposure during the first trimester is not significantly associated with major congenital malformations, which is reassuring, given that many patients take triptans before they realize that they are pregnant. During the second and third trimesters, triptan exposure is significantly associated with atonic uterus and increased blood loss during labor. In a 16-year registry, sumatriptan, naratriptan, and treximet were not associated with teratogenicity.

Nonpharmacological treatments, too, may help pregnant patients. Lifestyle management, including a regular sleep schedule, exercise routine, and diet, can be beneficial. Massage therapy may reduce stress, and cognitive-behavioral therapy and biofeedback are additional options. Behavioral therapy, however, should be initiated before the patient plans the pregnancy, said Dr. Nye. These therapies require training that a patient having an exacerbation of migraine is less likely to have the motivation to begin.

Many medications are transferred to infants through breast milk. The American Pediatric Association considers a relative infant dosing of less than 10% to be safe. A clinician or patient can look up a medication on websites such as LactMed to understand the relative infant dose and possible effects. Another helpful reference is Medications and Mothers’ Milk, said Dr. Nye. Acetaminophen, steroids, ibuprofen, riboflavin, indomethacin, ketorolac, and naproxen are generally safe during lactation. “Eletriptan is the triptan that’s least likely to be in the breast milk,” said Dr. Nye. Aspirin, atenolol, ergotamine, and lithium, however, should be given with caution. The safety of amitriptyline, nortriptyline, and SSRIs during lactation is unknown.

Dr. Nye is on advisory boards for Alder, Allergan, Biohaven, electroCore, Pernix, and Xoc.

[email protected]

STOWE, VT. – A large and growing number of medications is available for the acute treatment of migraine. Effective acute treatment enables patients to re-engage in their work and other daily activities, as well as reducing the likelihood that their disease will progress from episodic to chronic migraine. Considering appropriate routes of delivery, assessing efficacy and tolerability, and communicating well with the patient are essential components in the acute treatment of migraine, according to Barbara L. Nye, MD, assistant professor of neurology at the Geisel School of Medicine at Dartmouth, Hanover, N.H.. Dr. Nye discussed the acute treatment of migraine at the annual meeting of the Headache Cooperative of New England.

Choosing an initial treatment

Nonspecific medications are perhaps the first treatments to consider for a patient with acute migraine. This class includes NSAIDs such as naproxen sodium, piroxicam, diclofenac, celecoxib, and indomethacin. Emerging data indicate that some NSAIDs are associated with an increased risk of stroke, which is an important consideration as the population ages, said Dr. Nye. Other nonspecific options are neuroleptics such as prochlorperazine, metoclopramide, promethazine, and chlorpromazine. Many neuroleptics have sedative effects, however, so they do not necessarily help a patient return to function. Nevertheless, these drugs can be good rescue medications, said Dr. Nye.

Triptans are effective in the acute treatment of migraine, and seven drugs in this class are available. Most, such as rizatriptan, almotriptan, eletriptan, naratriptan, and frovatriptan, are available only as tablets. Other routes of delivery are available, however. Sumatriptan, for example, is available in injectable and intranasal formulations, and zolmitriptan is available as an orally dissolving tablet.

Another option to consider is dihydroergotamine (DHE), which has long been used for migraine. The injectable formulation of DHE can be cumbersome because it requires the patients with a headache to open a vial, draw the medication into a filter needle, and inject themselves, said Dr. Nye. “The nasal sprays that are available right now aren’t as effective as we’d like them to be,” she added. But overall, DHE is effective. Associated adverse events include flushing, nausea, and diarrhea.

Lasmiditan received approval from the Food and Drug Administration for the acute treatment of migraine in October 2019. Compared with placebo, the drug increases the likelihood of pain freedom and freedom from the most bothersome symptom at 2 hours. Driving tests indicated that patients were impaired for about 8 hours after treatment, and lasmiditan is a Schedule V drug. It is available in doses of 50 mg/day, 100 mg/day, and 200 mg/day.

The class of drugs known as the “gepants” provides further options. The most recently approved therapy in this class, which targets calcitonin gene–related peptide, is ubrogepant. Because the drug is metabolized through the CYP3A4 system, they are not appropriate for patients who use strong CYP3A4 inhibitors. The most common side effects are nausea, hypersensitivity reaction, and somnolence.

Neuromodulation can provide effective treatment without provoking side effects, said Dr. Nye. Options include transcutaneous supraorbital stimulation, single-pulse transcutaneous magnetic stimulation, noninvasive vagal nerve stimulation, and remote nonpainful stimulation.

If a patient presents during an acute attack, neurologists could consider using a nerve block. The latter may administer occipital nerve blocks, trigger point injections, auriculotemporal nerve blocks, and supraorbital and supratrochlear nerve blocks. This treatment can bring immediate relief, which is gratifying for patients and neurologists. But no consensus about which medications to use or how to administer them has been established. Neurologists most often use a combination of bupivacaine and lidocaine. Another possibility is a sphenopalatine ganglion nerve block, which requires treatment to be inserted through the nose. This treatment can be delivered in the office using the Sphenocath device or the Allevio device. Another device, the Tx360, is intended to enable patient self-administration.
 

Addressing treatment failure

If a patient returns and reports that the current treatment is ineffective, the neurologist must reevaluate the therapy. A helpful way to conduct this reassessment is to administer the Migraine Treatment Optimization Questionnaire (MTOQ), which was developed by Lipton et al., to the patient. Neurologists ask whether the patient can function normally 2 hours after treatment or whether the medication is, for example, causing a side effect that makes this outcome less likely. Other questions for the patient are whether the headache pain disappears within 2 hours and whether the medication provides consistent relief. Finally, the neurologist can ask whether the patient is comfortable taking the medication. A score lower than 2 on the MTOQ indicates that the acute treatment should be changed, said Dr. Nye.

Gastroparesis is common during migraine attacks. It is inadvisable to give an oral medication to a patient who vomits within 20 minutes of attack onset, said Dr. Nye. “It’s a little less intuitive for those people who are nauseous immediately to think that that oral tablet is probably going to sit in their stomach and not get absorbed in the intestines as intended.” Nasal sprays, injectable medicines, and oral dissolving tablets are appropriate options for patients with gastroparesis.
 

Treating migraine during pregnancy

Special consideration must be given to treatment when the patient is pregnant. Decreased headache frequency is common in pregnancy, but not universal. Occipital nerve blocks are a good option for prevention and acute management in pregnant patients. They may be administered every 2 weeks. Sphenopalatine ganglion nerve block is another option, and it can be administered several times per week. Data “suggest that stacking the injections 2 or 3 days per week for up to 6 weeks can eliminate headaches for up to 6 months,” said Dr. Nye.

Tylenol is appropriate for acute headache in pregnant patients, “but we do warn about medication overuse headache and limiting its use.” Ondansetron and promethazine are acceptable treatments for nausea. Although ondansetron has less central activity than promethazine, and thus does not reduce the headache, it lessens nausea, said Dr. Nye.

Triptan exposure during the first trimester is not significantly associated with major congenital malformations, which is reassuring, given that many patients take triptans before they realize that they are pregnant. During the second and third trimesters, triptan exposure is significantly associated with atonic uterus and increased blood loss during labor. In a 16-year registry, sumatriptan, naratriptan, and treximet were not associated with teratogenicity.

Nonpharmacological treatments, too, may help pregnant patients. Lifestyle management, including a regular sleep schedule, exercise routine, and diet, can be beneficial. Massage therapy may reduce stress, and cognitive-behavioral therapy and biofeedback are additional options. Behavioral therapy, however, should be initiated before the patient plans the pregnancy, said Dr. Nye. These therapies require training that a patient having an exacerbation of migraine is less likely to have the motivation to begin.

Many medications are transferred to infants through breast milk. The American Pediatric Association considers a relative infant dosing of less than 10% to be safe. A clinician or patient can look up a medication on websites such as LactMed to understand the relative infant dose and possible effects. Another helpful reference is Medications and Mothers’ Milk, said Dr. Nye. Acetaminophen, steroids, ibuprofen, riboflavin, indomethacin, ketorolac, and naproxen are generally safe during lactation. “Eletriptan is the triptan that’s least likely to be in the breast milk,” said Dr. Nye. Aspirin, atenolol, ergotamine, and lithium, however, should be given with caution. The safety of amitriptyline, nortriptyline, and SSRIs during lactation is unknown.

Dr. Nye is on advisory boards for Alder, Allergan, Biohaven, electroCore, Pernix, and Xoc.

[email protected]

STOWE, VT. – A large and growing number of medications is available for the acute treatment of migraine. Effective acute treatment enables patients to re-engage in their work and other daily activities, as well as reducing the likelihood that their disease will progress from episodic to chronic migraine. Considering appropriate routes of delivery, assessing efficacy and tolerability, and communicating well with the patient are essential components in the acute treatment of migraine, according to Barbara L. Nye, MD, assistant professor of neurology at the Geisel School of Medicine at Dartmouth, Hanover, N.H.. Dr. Nye discussed the acute treatment of migraine at the annual meeting of the Headache Cooperative of New England.

Choosing an initial treatment

Nonspecific medications are perhaps the first treatments to consider for a patient with acute migraine. This class includes NSAIDs such as naproxen sodium, piroxicam, diclofenac, celecoxib, and indomethacin. Emerging data indicate that some NSAIDs are associated with an increased risk of stroke, which is an important consideration as the population ages, said Dr. Nye. Other nonspecific options are neuroleptics such as prochlorperazine, metoclopramide, promethazine, and chlorpromazine. Many neuroleptics have sedative effects, however, so they do not necessarily help a patient return to function. Nevertheless, these drugs can be good rescue medications, said Dr. Nye.

Triptans are effective in the acute treatment of migraine, and seven drugs in this class are available. Most, such as rizatriptan, almotriptan, eletriptan, naratriptan, and frovatriptan, are available only as tablets. Other routes of delivery are available, however. Sumatriptan, for example, is available in injectable and intranasal formulations, and zolmitriptan is available as an orally dissolving tablet.

Another option to consider is dihydroergotamine (DHE), which has long been used for migraine. The injectable formulation of DHE can be cumbersome because it requires the patients with a headache to open a vial, draw the medication into a filter needle, and inject themselves, said Dr. Nye. “The nasal sprays that are available right now aren’t as effective as we’d like them to be,” she added. But overall, DHE is effective. Associated adverse events include flushing, nausea, and diarrhea.

Lasmiditan received approval from the Food and Drug Administration for the acute treatment of migraine in October 2019. Compared with placebo, the drug increases the likelihood of pain freedom and freedom from the most bothersome symptom at 2 hours. Driving tests indicated that patients were impaired for about 8 hours after treatment, and lasmiditan is a Schedule V drug. It is available in doses of 50 mg/day, 100 mg/day, and 200 mg/day.

The class of drugs known as the “gepants” provides further options. The most recently approved therapy in this class, which targets calcitonin gene–related peptide, is ubrogepant. Because the drug is metabolized through the CYP3A4 system, they are not appropriate for patients who use strong CYP3A4 inhibitors. The most common side effects are nausea, hypersensitivity reaction, and somnolence.

Neuromodulation can provide effective treatment without provoking side effects, said Dr. Nye. Options include transcutaneous supraorbital stimulation, single-pulse transcutaneous magnetic stimulation, noninvasive vagal nerve stimulation, and remote nonpainful stimulation.

If a patient presents during an acute attack, neurologists could consider using a nerve block. The latter may administer occipital nerve blocks, trigger point injections, auriculotemporal nerve blocks, and supraorbital and supratrochlear nerve blocks. This treatment can bring immediate relief, which is gratifying for patients and neurologists. But no consensus about which medications to use or how to administer them has been established. Neurologists most often use a combination of bupivacaine and lidocaine. Another possibility is a sphenopalatine ganglion nerve block, which requires treatment to be inserted through the nose. This treatment can be delivered in the office using the Sphenocath device or the Allevio device. Another device, the Tx360, is intended to enable patient self-administration.
 

Addressing treatment failure

If a patient returns and reports that the current treatment is ineffective, the neurologist must reevaluate the therapy. A helpful way to conduct this reassessment is to administer the Migraine Treatment Optimization Questionnaire (MTOQ), which was developed by Lipton et al., to the patient. Neurologists ask whether the patient can function normally 2 hours after treatment or whether the medication is, for example, causing a side effect that makes this outcome less likely. Other questions for the patient are whether the headache pain disappears within 2 hours and whether the medication provides consistent relief. Finally, the neurologist can ask whether the patient is comfortable taking the medication. A score lower than 2 on the MTOQ indicates that the acute treatment should be changed, said Dr. Nye.

Gastroparesis is common during migraine attacks. It is inadvisable to give an oral medication to a patient who vomits within 20 minutes of attack onset, said Dr. Nye. “It’s a little less intuitive for those people who are nauseous immediately to think that that oral tablet is probably going to sit in their stomach and not get absorbed in the intestines as intended.” Nasal sprays, injectable medicines, and oral dissolving tablets are appropriate options for patients with gastroparesis.
 

Treating migraine during pregnancy

Special consideration must be given to treatment when the patient is pregnant. Decreased headache frequency is common in pregnancy, but not universal. Occipital nerve blocks are a good option for prevention and acute management in pregnant patients. They may be administered every 2 weeks. Sphenopalatine ganglion nerve block is another option, and it can be administered several times per week. Data “suggest that stacking the injections 2 or 3 days per week for up to 6 weeks can eliminate headaches for up to 6 months,” said Dr. Nye.

Tylenol is appropriate for acute headache in pregnant patients, “but we do warn about medication overuse headache and limiting its use.” Ondansetron and promethazine are acceptable treatments for nausea. Although ondansetron has less central activity than promethazine, and thus does not reduce the headache, it lessens nausea, said Dr. Nye.

Triptan exposure during the first trimester is not significantly associated with major congenital malformations, which is reassuring, given that many patients take triptans before they realize that they are pregnant. During the second and third trimesters, triptan exposure is significantly associated with atonic uterus and increased blood loss during labor. In a 16-year registry, sumatriptan, naratriptan, and treximet were not associated with teratogenicity.

Nonpharmacological treatments, too, may help pregnant patients. Lifestyle management, including a regular sleep schedule, exercise routine, and diet, can be beneficial. Massage therapy may reduce stress, and cognitive-behavioral therapy and biofeedback are additional options. Behavioral therapy, however, should be initiated before the patient plans the pregnancy, said Dr. Nye. These therapies require training that a patient having an exacerbation of migraine is less likely to have the motivation to begin.

Many medications are transferred to infants through breast milk. The American Pediatric Association considers a relative infant dosing of less than 10% to be safe. A clinician or patient can look up a medication on websites such as LactMed to understand the relative infant dose and possible effects. Another helpful reference is Medications and Mothers’ Milk, said Dr. Nye. Acetaminophen, steroids, ibuprofen, riboflavin, indomethacin, ketorolac, and naproxen are generally safe during lactation. “Eletriptan is the triptan that’s least likely to be in the breast milk,” said Dr. Nye. Aspirin, atenolol, ergotamine, and lithium, however, should be given with caution. The safety of amitriptyline, nortriptyline, and SSRIs during lactation is unknown.

Dr. Nye is on advisory boards for Alder, Allergan, Biohaven, electroCore, Pernix, and Xoc.

[email protected]

STOWE, VT – The preventive treatment of migraine has the potential to change patients’ lives and modify the trajectory of the disease, said Rebecca Burch, MD, staff attending neurologist at Brigham and Women’s Hospital in Boston. Clinical observation suggests that preventive treatment provides benefits for appropriately selected migraineurs, although few data confirm a modifying effect on disease course, she said at the Stowe Headache Symposium sponsored by the Headache Cooperative of New England. In her overview, Dr. Burch discussed when preventive treatment is appropriate, which patients are candidates for preventive therapy, and what the levels of evidence are for the preventive therapies.

Identifying candidates for preventive treatment

Migraine is the second most disabling condition worldwide and imposes a large social and economic burden, said Dr. Burch. Preventive therapy reduces the disability associated with migraine. It reduces headache frequency and, thus, the risk that episodic migraine will transform into chronic migraine. By reducing the number of headache days, preventive treatment also may reduce the overuse of acute medication, which is a risk factor for migraine chronification.

Neurologists can consider preventive therapy for migraineurs with frequent headaches, but the term “frequent” is not clearly defined. Common definitions include one headache per week and two headaches per month with significant disability. These definitions are based on expert consensus and do not have strong evidential support, said Dr. Burch. Preventive therapy also may be appropriate for migraineurs who overuse acute medication or who have failed acute medications. Special cases, such as patients with exceptional anxiety or disability, may also call for preventive treatment, said Dr. Burch.

Data suggest that preventive treatment for migraine is underused. The American Migraine Prevalence and Prevention study of 2007 found that half of patients who should be offered preventive treatment are currently receiving it. In 2016, the Chronic Migraine Epidemiology and Outcomes study found that 4.5% of chronic migraineurs take both acute and preventive treatment.

Other data published in Cephalalgia in 2015 indicate that adherence to migraine preventive treatment is approximately 20%. About 45% of patients discontinue medication because of side effects, and 45% cite lack of efficacy as their reason for discontinuation. Patients also mentioned cost, interactions with other medications, and the inconvenience of daily medication as other reasons for discontinuation.

Neurologists can take several steps to increase adherence to preventive treatment, said Dr. Burch. First, neurologists should confirm that patients want preventive medication. A clear discussion of the goals of preventive treatment is helpful as well. Furthermore, neurologists should explain that they are offering patients a trial, said Dr. Burch. The medication can be titrated slowly from a low dose to minimize side effects. Patients can be reassured that ineffective medications will be stopped. Neurologists can emphasize that their relationship with the patient is a partnership and that the treatment strategy will be improved over time.
 

Examining the evidence on treatments’ efficacy

Many drug classes, such as antiepileptics, antidepressants, beta blockers, neurotoxins, and calcitonin gene-related peptide (CGRP) antibodies, include therapies that are used as preventive treatments for migraine. When selecting a medication, a neurologist should start with one that is supported by Level A or Level B evidence, said Dr. Burch. Medications with Level A evidence include divalproex, topiramate, metoprolol, propranolol, erenumab, galcanezumab, fremanezumab, eptinezumab, and onabotulinumtoxinA. Medications with Level B evidence include amitriptyline, venlafaxine, memantine, lisinopril, and candesartan. Neurologists sometimes prescribe gabapentin and verapamil, although the evidence for them is Level U. Duloxetine, nortriptyline, and pregabalin also are used, but the evidence for them has not been evaluated. “We need more evidence in these areas,” said Dr. Burch.

Neurologists should consider access (e.g., cost and insurance coverage), efficacy, side effects, and comorbidities and contraindications when choosing a preventive therapy, she added. Verapamil and memantine are well tolerated and appropriate choices if the goal is to avoid side effects in general. If weight gain or fatigue is a concern, then topiramate and venlafaxine should be considered. Neurologists should avoid prescribing antiepileptic drugs if cognitive symptoms are a concern, said Dr. Burch. Beta blockers and venlafaxine would be better options in this case.

In clinical trials of CGRP therapies, the rates of adverse events were similar between the active and control arms. “But it’s become fairly clear that the clinical trials did not fully capture the side-effect profile that we are seeing in clinical practice,” said Dr. Burch. In a paper currently in review, she and her colleagues retrospectively studied 241 patients that they had treated with CGRP monoclonal antibodies at their headache center. The most common adverse events were constipation (43%), injection-site reaction (24%), muscle or joint pain (17%), and fatigue (15%). Furthermore, CGRP antagonists were associated with maternal hypertension, fetal growth restriction, and fetal mortality in animal studies. The current recommendation is to avoid CGRP monoclonal antibodies during pregnancy or in any patient who is at risk of becoming pregnant, said Dr. Burch.
 

How should neurologists assess preventive efficacy?

The assessment of a medication’s preventive efficacy “is a moving target in the headache world,” said Dr. Burch. “Historically, we have used headache days per month, and that is still, according to the International Headache Society clinical trials guidelines, how we should be judging whether a medication is working or not. But that doesn’t necessarily tell us what’s going to happen to an individual patient in front of us.”

In 2017, the Institute for Clinical Effectiveness Research compared data for old and new migraine treatments in a network meta-analysis. They all tended to reduce the number of monthly migraine days by one to two, compared with placebo. When one analyzes clinical trials of the drugs using this criterion, “most of these treatments come out about the same,” said Dr. Burch.

More recently, investigators have examined responder rates. They commonly report the proportions of patients who had a reduction in headache days of 50%, 75%, or 100%, for example. To extrapolate responder rates from the trial participants to the general population, a neurologist must know which groups of patients got worse on treatment, said Dr. Burch. Furthermore, the responder rates for older medications are unknown, because they were not examined. This situation makes comparisons of newer and older therapies more complicated.

Phase 3 trials of the CGRP drugs included analyses of the therapies’ 50% responder rates. This rate was about 42% for the 70-mg dose of erenumab and 50% for the 140-mg dose. The 50% responder rates for fremanezumab were 47.7% for the 225-mg dose and 44.4% for the 675-mg dose. In two trials of galcanezumab, the 50% responder rate for the 120-mg dose was approximately 60%, and the rate for the 240-mg dose was about 59%. The 50% responder rates for eptinezumab were 50% for the 100-mg dose and 56% for the 300-mg dose. The 50% responder rate across all trials was around 50%-60% in the active group, which is roughly 25% over the placebo group, said Dr. Burch.

Another measurement of efficacy is the efficacy-to-harm ratio, which is derived from the number needed to treat and the number needed to harm. To calculate this ratio, however, harm needs to be assessed adequately during a clinical trial. Although the ratio can provide a clinically relevant overview of a drug’s effects, patients may differ from each other in the way they evaluate efficacy and harm.

In addition, many questions about preventive treatment of migraine have no clear answers yet. It is uncertain, for example, how long a patient should receive preventive treatment and when treatment should be withdrawn, said Dr. Burch. “Can we expect that a lot of people are going to need to be on it for life, or is there a subpopulation who will get better and [for whom] we can withdraw [treatment]?” she asked. “How do we identify them?” Also, more data are needed before neurologists can understand why a given patient responds to one treatment, but not to another. It is difficult to predict which patients will respond to which treatments. Finally, it remains unclear how much of patients’ improvement can be attributed to regression to the mean, rather than preventive treatment.

[email protected]

STOWE, VT – The preventive treatment of migraine has the potential to change patients’ lives and modify the trajectory of the disease, said Rebecca Burch, MD, staff attending neurologist at Brigham and Women’s Hospital in Boston. Clinical observation suggests that preventive treatment provides benefits for appropriately selected migraineurs, although few data confirm a modifying effect on disease course, she said at the Stowe Headache Symposium sponsored by the Headache Cooperative of New England. In her overview, Dr. Burch discussed when preventive treatment is appropriate, which patients are candidates for preventive therapy, and what the levels of evidence are for the preventive therapies.

Identifying candidates for preventive treatment

Migraine is the second most disabling condition worldwide and imposes a large social and economic burden, said Dr. Burch. Preventive therapy reduces the disability associated with migraine. It reduces headache frequency and, thus, the risk that episodic migraine will transform into chronic migraine. By reducing the number of headache days, preventive treatment also may reduce the overuse of acute medication, which is a risk factor for migraine chronification.

Neurologists can consider preventive therapy for migraineurs with frequent headaches, but the term “frequent” is not clearly defined. Common definitions include one headache per week and two headaches per month with significant disability. These definitions are based on expert consensus and do not have strong evidential support, said Dr. Burch. Preventive therapy also may be appropriate for migraineurs who overuse acute medication or who have failed acute medications. Special cases, such as patients with exceptional anxiety or disability, may also call for preventive treatment, said Dr. Burch.

Data suggest that preventive treatment for migraine is underused. The American Migraine Prevalence and Prevention study of 2007 found that half of patients who should be offered preventive treatment are currently receiving it. In 2016, the Chronic Migraine Epidemiology and Outcomes study found that 4.5% of chronic migraineurs take both acute and preventive treatment.

Other data published in Cephalalgia in 2015 indicate that adherence to migraine preventive treatment is approximately 20%. About 45% of patients discontinue medication because of side effects, and 45% cite lack of efficacy as their reason for discontinuation. Patients also mentioned cost, interactions with other medications, and the inconvenience of daily medication as other reasons for discontinuation.

Neurologists can take several steps to increase adherence to preventive treatment, said Dr. Burch. First, neurologists should confirm that patients want preventive medication. A clear discussion of the goals of preventive treatment is helpful as well. Furthermore, neurologists should explain that they are offering patients a trial, said Dr. Burch. The medication can be titrated slowly from a low dose to minimize side effects. Patients can be reassured that ineffective medications will be stopped. Neurologists can emphasize that their relationship with the patient is a partnership and that the treatment strategy will be improved over time.
 

Examining the evidence on treatments’ efficacy

Many drug classes, such as antiepileptics, antidepressants, beta blockers, neurotoxins, and calcitonin gene-related peptide (CGRP) antibodies, include therapies that are used as preventive treatments for migraine. When selecting a medication, a neurologist should start with one that is supported by Level A or Level B evidence, said Dr. Burch. Medications with Level A evidence include divalproex, topiramate, metoprolol, propranolol, erenumab, galcanezumab, fremanezumab, eptinezumab, and onabotulinumtoxinA. Medications with Level B evidence include amitriptyline, venlafaxine, memantine, lisinopril, and candesartan. Neurologists sometimes prescribe gabapentin and verapamil, although the evidence for them is Level U. Duloxetine, nortriptyline, and pregabalin also are used, but the evidence for them has not been evaluated. “We need more evidence in these areas,” said Dr. Burch.

Neurologists should consider access (e.g., cost and insurance coverage), efficacy, side effects, and comorbidities and contraindications when choosing a preventive therapy, she added. Verapamil and memantine are well tolerated and appropriate choices if the goal is to avoid side effects in general. If weight gain or fatigue is a concern, then topiramate and venlafaxine should be considered. Neurologists should avoid prescribing antiepileptic drugs if cognitive symptoms are a concern, said Dr. Burch. Beta blockers and venlafaxine would be better options in this case.

In clinical trials of CGRP therapies, the rates of adverse events were similar between the active and control arms. “But it’s become fairly clear that the clinical trials did not fully capture the side-effect profile that we are seeing in clinical practice,” said Dr. Burch. In a paper currently in review, she and her colleagues retrospectively studied 241 patients that they had treated with CGRP monoclonal antibodies at their headache center. The most common adverse events were constipation (43%), injection-site reaction (24%), muscle or joint pain (17%), and fatigue (15%). Furthermore, CGRP antagonists were associated with maternal hypertension, fetal growth restriction, and fetal mortality in animal studies. The current recommendation is to avoid CGRP monoclonal antibodies during pregnancy or in any patient who is at risk of becoming pregnant, said Dr. Burch.
 

How should neurologists assess preventive efficacy?

The assessment of a medication’s preventive efficacy “is a moving target in the headache world,” said Dr. Burch. “Historically, we have used headache days per month, and that is still, according to the International Headache Society clinical trials guidelines, how we should be judging whether a medication is working or not. But that doesn’t necessarily tell us what’s going to happen to an individual patient in front of us.”

In 2017, the Institute for Clinical Effectiveness Research compared data for old and new migraine treatments in a network meta-analysis. They all tended to reduce the number of monthly migraine days by one to two, compared with placebo. When one analyzes clinical trials of the drugs using this criterion, “most of these treatments come out about the same,” said Dr. Burch.

More recently, investigators have examined responder rates. They commonly report the proportions of patients who had a reduction in headache days of 50%, 75%, or 100%, for example. To extrapolate responder rates from the trial participants to the general population, a neurologist must know which groups of patients got worse on treatment, said Dr. Burch. Furthermore, the responder rates for older medications are unknown, because they were not examined. This situation makes comparisons of newer and older therapies more complicated.

Phase 3 trials of the CGRP drugs included analyses of the therapies’ 50% responder rates. This rate was about 42% for the 70-mg dose of erenumab and 50% for the 140-mg dose. The 50% responder rates for fremanezumab were 47.7% for the 225-mg dose and 44.4% for the 675-mg dose. In two trials of galcanezumab, the 50% responder rate for the 120-mg dose was approximately 60%, and the rate for the 240-mg dose was about 59%. The 50% responder rates for eptinezumab were 50% for the 100-mg dose and 56% for the 300-mg dose. The 50% responder rate across all trials was around 50%-60% in the active group, which is roughly 25% over the placebo group, said Dr. Burch.

Another measurement of efficacy is the efficacy-to-harm ratio, which is derived from the number needed to treat and the number needed to harm. To calculate this ratio, however, harm needs to be assessed adequately during a clinical trial. Although the ratio can provide a clinically relevant overview of a drug’s effects, patients may differ from each other in the way they evaluate efficacy and harm.

In addition, many questions about preventive treatment of migraine have no clear answers yet. It is uncertain, for example, how long a patient should receive preventive treatment and when treatment should be withdrawn, said Dr. Burch. “Can we expect that a lot of people are going to need to be on it for life, or is there a subpopulation who will get better and [for whom] we can withdraw [treatment]?” she asked. “How do we identify them?” Also, more data are needed before neurologists can understand why a given patient responds to one treatment, but not to another. It is difficult to predict which patients will respond to which treatments. Finally, it remains unclear how much of patients’ improvement can be attributed to regression to the mean, rather than preventive treatment.

[email protected]

STOWE, VT – The preventive treatment of migraine has the potential to change patients’ lives and modify the trajectory of the disease, said Rebecca Burch, MD, staff attending neurologist at Brigham and Women’s Hospital in Boston. Clinical observation suggests that preventive treatment provides benefits for appropriately selected migraineurs, although few data confirm a modifying effect on disease course, she said at the Stowe Headache Symposium sponsored by the Headache Cooperative of New England. In her overview, Dr. Burch discussed when preventive treatment is appropriate, which patients are candidates for preventive therapy, and what the levels of evidence are for the preventive therapies.

Identifying candidates for preventive treatment

Migraine is the second most disabling condition worldwide and imposes a large social and economic burden, said Dr. Burch. Preventive therapy reduces the disability associated with migraine. It reduces headache frequency and, thus, the risk that episodic migraine will transform into chronic migraine. By reducing the number of headache days, preventive treatment also may reduce the overuse of acute medication, which is a risk factor for migraine chronification.

Neurologists can consider preventive therapy for migraineurs with frequent headaches, but the term “frequent” is not clearly defined. Common definitions include one headache per week and two headaches per month with significant disability. These definitions are based on expert consensus and do not have strong evidential support, said Dr. Burch. Preventive therapy also may be appropriate for migraineurs who overuse acute medication or who have failed acute medications. Special cases, such as patients with exceptional anxiety or disability, may also call for preventive treatment, said Dr. Burch.

Data suggest that preventive treatment for migraine is underused. The American Migraine Prevalence and Prevention study of 2007 found that half of patients who should be offered preventive treatment are currently receiving it. In 2016, the Chronic Migraine Epidemiology and Outcomes study found that 4.5% of chronic migraineurs take both acute and preventive treatment.

Other data published in Cephalalgia in 2015 indicate that adherence to migraine preventive treatment is approximately 20%. About 45% of patients discontinue medication because of side effects, and 45% cite lack of efficacy as their reason for discontinuation. Patients also mentioned cost, interactions with other medications, and the inconvenience of daily medication as other reasons for discontinuation.

Neurologists can take several steps to increase adherence to preventive treatment, said Dr. Burch. First, neurologists should confirm that patients want preventive medication. A clear discussion of the goals of preventive treatment is helpful as well. Furthermore, neurologists should explain that they are offering patients a trial, said Dr. Burch. The medication can be titrated slowly from a low dose to minimize side effects. Patients can be reassured that ineffective medications will be stopped. Neurologists can emphasize that their relationship with the patient is a partnership and that the treatment strategy will be improved over time.
 

Examining the evidence on treatments’ efficacy

Many drug classes, such as antiepileptics, antidepressants, beta blockers, neurotoxins, and calcitonin gene-related peptide (CGRP) antibodies, include therapies that are used as preventive treatments for migraine. When selecting a medication, a neurologist should start with one that is supported by Level A or Level B evidence, said Dr. Burch. Medications with Level A evidence include divalproex, topiramate, metoprolol, propranolol, erenumab, galcanezumab, fremanezumab, eptinezumab, and onabotulinumtoxinA. Medications with Level B evidence include amitriptyline, venlafaxine, memantine, lisinopril, and candesartan. Neurologists sometimes prescribe gabapentin and verapamil, although the evidence for them is Level U. Duloxetine, nortriptyline, and pregabalin also are used, but the evidence for them has not been evaluated. “We need more evidence in these areas,” said Dr. Burch.

Neurologists should consider access (e.g., cost and insurance coverage), efficacy, side effects, and comorbidities and contraindications when choosing a preventive therapy, she added. Verapamil and memantine are well tolerated and appropriate choices if the goal is to avoid side effects in general. If weight gain or fatigue is a concern, then topiramate and venlafaxine should be considered. Neurologists should avoid prescribing antiepileptic drugs if cognitive symptoms are a concern, said Dr. Burch. Beta blockers and venlafaxine would be better options in this case.

In clinical trials of CGRP therapies, the rates of adverse events were similar between the active and control arms. “But it’s become fairly clear that the clinical trials did not fully capture the side-effect profile that we are seeing in clinical practice,” said Dr. Burch. In a paper currently in review, she and her colleagues retrospectively studied 241 patients that they had treated with CGRP monoclonal antibodies at their headache center. The most common adverse events were constipation (43%), injection-site reaction (24%), muscle or joint pain (17%), and fatigue (15%). Furthermore, CGRP antagonists were associated with maternal hypertension, fetal growth restriction, and fetal mortality in animal studies. The current recommendation is to avoid CGRP monoclonal antibodies during pregnancy or in any patient who is at risk of becoming pregnant, said Dr. Burch.
 

How should neurologists assess preventive efficacy?

The assessment of a medication’s preventive efficacy “is a moving target in the headache world,” said Dr. Burch. “Historically, we have used headache days per month, and that is still, according to the International Headache Society clinical trials guidelines, how we should be judging whether a medication is working or not. But that doesn’t necessarily tell us what’s going to happen to an individual patient in front of us.”

In 2017, the Institute for Clinical Effectiveness Research compared data for old and new migraine treatments in a network meta-analysis. They all tended to reduce the number of monthly migraine days by one to two, compared with placebo. When one analyzes clinical trials of the drugs using this criterion, “most of these treatments come out about the same,” said Dr. Burch.

More recently, investigators have examined responder rates. They commonly report the proportions of patients who had a reduction in headache days of 50%, 75%, or 100%, for example. To extrapolate responder rates from the trial participants to the general population, a neurologist must know which groups of patients got worse on treatment, said Dr. Burch. Furthermore, the responder rates for older medications are unknown, because they were not examined. This situation makes comparisons of newer and older therapies more complicated.

Phase 3 trials of the CGRP drugs included analyses of the therapies’ 50% responder rates. This rate was about 42% for the 70-mg dose of erenumab and 50% for the 140-mg dose. The 50% responder rates for fremanezumab were 47.7% for the 225-mg dose and 44.4% for the 675-mg dose. In two trials of galcanezumab, the 50% responder rate for the 120-mg dose was approximately 60%, and the rate for the 240-mg dose was about 59%. The 50% responder rates for eptinezumab were 50% for the 100-mg dose and 56% for the 300-mg dose. The 50% responder rate across all trials was around 50%-60% in the active group, which is roughly 25% over the placebo group, said Dr. Burch.

Another measurement of efficacy is the efficacy-to-harm ratio, which is derived from the number needed to treat and the number needed to harm. To calculate this ratio, however, harm needs to be assessed adequately during a clinical trial. Although the ratio can provide a clinically relevant overview of a drug’s effects, patients may differ from each other in the way they evaluate efficacy and harm.

In addition, many questions about preventive treatment of migraine have no clear answers yet. It is uncertain, for example, how long a patient should receive preventive treatment and when treatment should be withdrawn, said Dr. Burch. “Can we expect that a lot of people are going to need to be on it for life, or is there a subpopulation who will get better and [for whom] we can withdraw [treatment]?” she asked. “How do we identify them?” Also, more data are needed before neurologists can understand why a given patient responds to one treatment, but not to another. It is difficult to predict which patients will respond to which treatments. Finally, it remains unclear how much of patients’ improvement can be attributed to regression to the mean, rather than preventive treatment.

[email protected]

Chronic pain is a worldwide cause of impairment. According to data from the 2016 National Health Interview Survey, an estimated 50 million American adults suffer from chronic pain, with 19.6 million adults suffering from high-impact chronic pain.¹ This phenomenon is particularly prevalent in the older population. More than 25% of adults aged 65 to 74 years reported that they were often in pain in the past 3 months compared with just 10% of those adults between the ages of 18 and 44 years.²

The economic burdens of chronic pain disorders are well known. In 2010, Gaskin and Richard found that chronic pain has far-reaching consequences for the US economy, ranging from direct health care costs to lost productivity. This study estimated additional health care costs at about $300 billion yearly and lost productivity at $300 billion, bringing total annual costs to about $600 billion. This expense is more than heart disease alone ($309 billion), and cancer and diabetes mellitus ($243 billion and $188 billion respectively) combined.³

Opioid medications are powerful and effective pain-reducing agents that are indicated for short-term acute pain or long-term in the management of chronic, severe cancer-related pain.⁴ Although efficacious, use of these medications carries with it the inherent risks of abuse, misuse, addiction, and overdose.⁵ Since 1999, opioid-related overdose deaths have been on the rise. The CDC estimated that > 15,000 deaths were attributable specifically to prescription opioids in 2015.⁶ The estimates had risen to > 17,000 deaths in 2017, with the number increasing since that time.⁷ Cumulatively, the CDC estimates that > 200,000 deaths in the US between 1999 and 2017 are attributed to prescription opioid overdose, clearly marking this trend as a growing nationwide epidemic.⁸

In 2016, Florence and colleagues estimated costs associated with opioid overdose to be just shy of $80 billion in 2013 dollars.⁹ In October 2017, the US Department of Health and Human Services declared the opioid epidemic a public health emergency and committed $900 million to combating the crisis.¹⁰

An abundance of data exist analyzing outpatient prescribing and its impacts on opioid dependence, particularly postoperatively. A study by Brummett and colleagues indicated that the incidence of new persistent opioid use in patients who underwent surgery was 5.9% to 6.5% and did not differ between major and minor surgical procedures. This study concluded that new opioid use could be considered one of the most common complications after elective surgery.¹¹ Similarly, in 2017 Makary and colleagues found that surgeons tend to overprescribe pain medications after procedures; some prescribing as many as 50 to 60 tablets to control pain after simple procedures.¹² This is in stark contrast to pain guideline recommendations of no more than 10 tablets for most standard operative procedures.¹³

Sun and colleagues conducted a retrospective analysis of health care claims data in more than 18 million opioid-naïve patients who did and did not undergo surgery. Seven of the 11 surgical procedures were associated with an increased risk of chronic opioid use. The highest incidence of chronic opioid use in the first postoperative year was for total hip arthroplasty (1.4%, OR 5.10; 95% CI, 1.29-1.53). The study found that the risk factors most associated with chronic opioid use after surgery were male sex, aged > 50 years, and preoperative history of drug abuse, alcohol abuse, or depression, along with benzodiazepine use or antidepressant use.¹⁴ In a 2018 cohort study that evaluated predictors associated with transitioning to incident chronic opioid therapy, 4 factors were identified. These included opioid duration of action (adjusted odds ratio [AOR], 12.28; 95% CI, 8.1-06-18.72), the parent opioid compound (eg, tramadol vs codeine; AOR, 7.26; 95% CI, 5.20-10.13), the presence of conditions that are very likely to cause chronic pain (AOR, 5.47; 95% CI, 3.89-7.68), and drug use disorders (AOR, 4.02; 95% CI, 2.53-6.40).¹⁵

While there has been research into outpatient risk factors and medical practices that may contribute to chronic opioid use, a relative paucity of data exists on the contribution of hospitalization and inpatient opioid use on patient outcomes. A 2014 Canadian study assessed the impact of opioid use in the intensive care unit (ICU) on opioid use after discharge.¹⁶ This study included more than 2,500 patients who were admitted to a Canadian ICU between 2005 and 2008, and then followed after discharge for 48 months to quantify chronic opioid use. Nonopioid users increased from 87.8% in the early post-ICU period to 95.6% at 48 months after discharge. Preadmission chronic opioid use and prolonged hospital length of stay (LOS) were found to be associated with an increased risk of chronic opioid use after discharge.¹⁶ To date, there are no published studies that analyze the incidence of opioid-naïve veterans who convert to chronic opioid use after receiving opioids during an acute hospitalization.

In this retrospective analysis, we analyze the incidence of chronic opioid use after administration of opioids in the ICU as well as a variety of risk factors that may influence conversion to chronic opioid use.

Methods

This analysis was a single center, retrospective chart review conducted for patients admitted between July 1, 2017 and December 31, 2017 at the US Department of Veterans Affairs (VA) Michael E. DeBakey VA Medical Center (MEDVAMC) in Houston, Texas. MEDVAMC is a 538-bed academic\teaching hospital serving about 130,000 veterans in Southeast Texas. The hospital has 3 ICUs (medical, cardiovascular, and surgical) and 38 total ICU beds. The study was approved by the Baylor College of Medicine Institutional Review Board and MEDVAMC Research and Development Review Board. Informed consent was not required.

Inclusion criteria consisted of patients aged ≥ 18 years admitted to the ICU in the above-specified time frame, who were administered a continuous infusion of an opioid for at least 12 hours. Patients were excluded if they were not opioid naïve prior to admission, defined as receiving > 30 days of opioids in the prior 12 months. Patients who died during hospital admission, never received an opioid despite having an active order, were hospital-to-hospital transfers, or were still admitted at the time of data collection were excluded from the analysis.

All pertinent data were collected using the VA Computerized Patient Record System (CPRS) and the Critical Care Manager (Picis Clinical Solutions) ICU monitoring application. Critical Care Manager was used to track the time frame, duration, and amounts of opioid infusions administered in the ICU. Patient demographic and preadmission data, including date of birth, age, race, history of substance use/alcohol use disorder (defined as a previous diagnosis) and previous opioid prescriptions within the past year were recorded. For the inpatient admission, the ICU LOS, hospital LOS, primary admission diagnosis, type of opioid medication administered, and total duration and dose of opioid administered were collected. After discharge, opioid medication fill data at 3, 6, and 12 months were collected. This information included names of any outpatient opioids filled, dosage unit, quantity, day supply, and number of refills.

The primary outcome for this study was to determine the incidence of chronic opioid use at 3, 6, and 12 months after discharge, defined as the percentage of patients receiving outpatient opioid prescriptions at each time point. Analyses were conducted to observe the effect of age, race, history of substance use or history of alcohol use (International Classification of Diseases documented diagnosis, 9th edition), ICU type (medical, surgical, or cardiovascular), surgical/nonsurgical admission, ICU LOS, hospital LOS, total time, and amount of opioids administered during admission on risk of conversion to chronic opioid use.

Descriptive statistics were calculated to analyze the incidence of chronic opioid use. Univariate logistic regression analysis, including ORs, 95% CIs, and P values, was conducted to determine the effects of the risk factors noted earlier on chronic opioid use at each time point. A multivariate logistic regression model was performed to assess the effect of multiple independent variables on opioid use at 3, 6, and 12 months. Statistical analysis was performed using StataCorp Stata SE.

Results

During the study period, 330 patients were admitted to the ICU. After applying inclusion/exclusion criteria, 118 patients were included in the final analysis. The most frequent reasons for exclusion from the study were patient death (n = 77), a past history of opioid use (n = 56), and not having received an opioid infusion for at least 12 hours (n = 68). The average age of the patients included was 67 years (Table 1). A total of 14% and 9% of patients, respectively, had a diagnosis of alcohol use disorder or substance use disorder recorded in CPRS. After admission, the most common location for these patients was the surgical ICU (65%). All patients were male. The average hospital LOS was 18.6 days , and the ICU LOS was 8.3 days. The average duration of administration for the opioid (fentanyl) infusion was 63 hours, and the average amount of fentanyl administered to each patient was 57.1 mcg/h.

The incidence of opioid-naïve patients receiving opioids after discharge was 76.3% (n = 90) at 3 months, 19.5% (n = 23) at 6 months and 7.6% (n = 9) at 12 months (Figure). The daily morphine milligram equivalent (MME) of patients prescribed opioids at 3, 6, and 12 months was similar (3 months, 22.7; 6 months, 19.7; 12 months, 20.9). In the univariate regression analysis, several variables were found to be associated with converting to chronic opioid use. Prior history of alcohol use disorder (OR, 0.3; 95% CI, 0.10-0.88; P = .03), ICU type (OR, 3.9; 95% CI, 1.73-8.75; P = .001) and ICU LOS (OR, 0.88; 95% CI, 0.81-0.95; P = .01) had a statistically significant association on opioid use at 3 months. (Table 2). No variables evaluated had a statistically significant effect on chronic opioid use at 6 months, and only age (OR 0.93; 95% CI. 0.87-0.99; P = .02) was statistically significant at 12 months. In the multivariate logistic regression analysis, history of alcohol abuse, admission for surgery, and hospital LOS were significant at 3 months (Table 3).

Discussion

In this single-center analysis conducted at a VA academic hospital of opioid-naïve patients who were administered opioids in the ICU, the incidence of patients subsequently receiving outpatient opioid prescriptions at 12 months after discharge was 7.6%. There also was a decrease in the amount of opioids received by patients (daily MME) after discharge at 3, 6, and 12 months. This trend did not demonstrate the propensity for inpatient opioid use to convert opioid-naïve patients to chronic opioid users.

The most common outpatient opioids prescribed were hydrocodone/acetaminophen, morphine, and tramadol. Logistic regression showed few factors that correlated significantly with opioid use in the long-term (12 month) period. This finding is a deviation from the findings of Yaffe and colleagues who found hospital LOS to be one of the only predictors of long-term opioid use in their population (defined as use at 48 months).¹⁶ One important difference between our study and the Yaffe and colleagues study was that they evaluated all patients who were admitted to the ICU, regardless of the exposure to opioids during their inpatient stay. Consequently, this difference may have resulted in the differences in findings.

Strengths and Limitations

Location was a strength of our study, as this analysis was conducted at an integrated health care system that provides comprehensive inpatient and outpatient care. The VA uses a closed electronic health record, which allowed patients to be followed both in the inpatient and outpatient settings to determine which medications were prescribed at each time. In other health care systems this information would have been difficult to follow as patients often fill outpatient prescriptions at community pharmacies not affiliated with the treating hospital. However, any patient not using a VA prescriber for subsequent opioid prescriptions or patients who received opioids through other sources would not have had their continued opioid use captured. These data may be available in the states prescription monitoring program, but it was not available to query for research at this time.

This study also excluded chronic opioid users, which could have been another confounding factor to account for when analyzing the results. However, the primary objective of the study was to determine the impact of opioids prescribed in the ICU on converting previous opioid-naïve patients to chronic users. Finally, a multivariate logistic regression was incorporated to assess for factors that may predispose certain patients to convert to chronic opioid users. This analysis served to extend the applicability of our study by not only analyzing whether receiving opioids in the ICU contributed to chronic opioid use in the long-term, but also which populations may be at greatest risk. This information can be used in the future to target harm-reduction efforts toward high-risk hospitalized patients.

One limitation of this study was that it was conducted as a retrospective, single-center chart review in Houston, Texas. Because this was not a randomized controlled trial, it is difficult to imply any causation between exposure to opioids in the ICU and chronic use. In addition, because this study was conducted at a single site, the results may not be able to be generalized to other populations. VA populations tend to be elderly and predominantly male, as was reflected by the study population. These factors, along with regional variability in patient characteristics, may limit the generalizability of this study to older male patients located in Southeast Texas or other similar populations. Other limitations of this study also included the small sample size, limited period of follow-up obtained, and that other comorbidity information (pain scores during stay, use of nonopioid pain medications, past history of anxiety or depression, or other acute illnesses or surgeries that may have required opioid therapy during admission) was not collected.

This study was only able to review 118 patients for a follow-up duration of 1 year. In the Yaffe and colleagues study, more than 2,500 patients were followed over 4 years, which provided a more long-term overview of the clinical course of these patients and may be another reason for discrepant findings. However, this study did not actually assess the impact on administration of opioids on the development of chronic opioid use.¹⁶ Finally, the biggest limitation to this study may be the potential for confounding discharge prescriptions. After discharge, patients’ prescriptions were evaluated from discharge to 3 months, in between 3 and 6 months, and between 6 and 12 months for the presence of an opioid prescription. Due to this methodology, any opioid prescription a patient was discharged with was counted in the 3-month time point. Since many patients included in the study were admitted to the surgical ICU (65%), it was logical that they were discharged with opioids after their procedure. While including the immediate postdischarge prescription data was useful for evaluating the decrease in opioid use and incidence over time, it did cause the 3-month time point to appear overly inflated, potentially signaling that at 3 months after discharge many of these patients were still requiring opioid use.

The Society of Critical Care Medicine still recommends opioids as first-line therapy for non-neuropathic pain in the ICU setting.¹⁷ Additionally, postoperative pain can be difficult to manage in the surgical population and is often treated with opioids, though treatment with multimodal pain regimens is becoming more common.¹⁸ It is difficult to imagine that a finding that implicates opioid use in the hospital with conversion to chronic opioid use would prompt a cessation in the use of opioid in these settings, especially in the context of analgosedation related to mechanically ventilated patients. However, it would be plausible to use this knowledge to advocate for opioid-sparing therapies and consideration for weaning individuals at high risk for misuse after discharge from opioid-containing sedation or analgesia regimens in a timelier manner.

Though our findings did not show a clinically relevant increase in chronic opioid users, clinicians can still use this information to encourage targeted education and closer monitoring for those patients deemed as high risk at discharge to prevent unnecessary prolonged opioid use. By having more frequent follow-up in pain clinics, switching patients to nonopioid therapies after discharge, and ensuring high-risk patients are discharged with naloxone rescue kits, it would be possible to drastically reduce the number of potential overdoses for patients who previously required opioid therapy in the ICU.

Conclusion

After discharge, 7.6% of previously opioid-naïve patients who were treated with opioids in the ICU were still receiving prescriptions for opioids at 12 months. These findings did not suggest a clinically significant increase in the incidence of chronic opioid use after inpatient administration of opioids. However, these results prompt the need for larger, prospective, multicenter studies to evaluate the effect on hospitalization on converting to chronic opioid use and a deeper evaluation of other potential risk factors that may be present.

Chronic pain is a worldwide cause of impairment. According to data from the 2016 National Health Interview Survey, an estimated 50 million American adults suffer from chronic pain, with 19.6 million adults suffering from high-impact chronic pain.¹ This phenomenon is particularly prevalent in the older population. More than 25% of adults aged 65 to 74 years reported that they were often in pain in the past 3 months compared with just 10% of those adults between the ages of 18 and 44 years.²

The economic burdens of chronic pain disorders are well known. In 2010, Gaskin and Richard found that chronic pain has far-reaching consequences for the US economy, ranging from direct health care costs to lost productivity. This study estimated additional health care costs at about $300 billion yearly and lost productivity at $300 billion, bringing total annual costs to about $600 billion. This expense is more than heart disease alone ($309 billion), and cancer and diabetes mellitus ($243 billion and $188 billion respectively) combined.³

Opioid medications are powerful and effective pain-reducing agents that are indicated for short-term acute pain or long-term in the management of chronic, severe cancer-related pain.⁴ Although efficacious, use of these medications carries with it the inherent risks of abuse, misuse, addiction, and overdose.⁵ Since 1999, opioid-related overdose deaths have been on the rise. The CDC estimated that > 15,000 deaths were attributable specifically to prescription opioids in 2015.⁶ The estimates had risen to > 17,000 deaths in 2017, with the number increasing since that time.⁷ Cumulatively, the CDC estimates that > 200,000 deaths in the US between 1999 and 2017 are attributed to prescription opioid overdose, clearly marking this trend as a growing nationwide epidemic.⁸

In 2016, Florence and colleagues estimated costs associated with opioid overdose to be just shy of $80 billion in 2013 dollars.⁹ In October 2017, the US Department of Health and Human Services declared the opioid epidemic a public health emergency and committed $900 million to combating the crisis.¹⁰

An abundance of data exist analyzing outpatient prescribing and its impacts on opioid dependence, particularly postoperatively. A study by Brummett and colleagues indicated that the incidence of new persistent opioid use in patients who underwent surgery was 5.9% to 6.5% and did not differ between major and minor surgical procedures. This study concluded that new opioid use could be considered one of the most common complications after elective surgery.¹¹ Similarly, in 2017 Makary and colleagues found that surgeons tend to overprescribe pain medications after procedures; some prescribing as many as 50 to 60 tablets to control pain after simple procedures.¹² This is in stark contrast to pain guideline recommendations of no more than 10 tablets for most standard operative procedures.¹³

Sun and colleagues conducted a retrospective analysis of health care claims data in more than 18 million opioid-naïve patients who did and did not undergo surgery. Seven of the 11 surgical procedures were associated with an increased risk of chronic opioid use. The highest incidence of chronic opioid use in the first postoperative year was for total hip arthroplasty (1.4%, OR 5.10; 95% CI, 1.29-1.53). The study found that the risk factors most associated with chronic opioid use after surgery were male sex, aged > 50 years, and preoperative history of drug abuse, alcohol abuse, or depression, along with benzodiazepine use or antidepressant use.¹⁴ In a 2018 cohort study that evaluated predictors associated with transitioning to incident chronic opioid therapy, 4 factors were identified. These included opioid duration of action (adjusted odds ratio [AOR], 12.28; 95% CI, 8.1-06-18.72), the parent opioid compound (eg, tramadol vs codeine; AOR, 7.26; 95% CI, 5.20-10.13), the presence of conditions that are very likely to cause chronic pain (AOR, 5.47; 95% CI, 3.89-7.68), and drug use disorders (AOR, 4.02; 95% CI, 2.53-6.40).¹⁵

While there has been research into outpatient risk factors and medical practices that may contribute to chronic opioid use, a relative paucity of data exists on the contribution of hospitalization and inpatient opioid use on patient outcomes. A 2014 Canadian study assessed the impact of opioid use in the intensive care unit (ICU) on opioid use after discharge.¹⁶ This study included more than 2,500 patients who were admitted to a Canadian ICU between 2005 and 2008, and then followed after discharge for 48 months to quantify chronic opioid use. Nonopioid users increased from 87.8% in the early post-ICU period to 95.6% at 48 months after discharge. Preadmission chronic opioid use and prolonged hospital length of stay (LOS) were found to be associated with an increased risk of chronic opioid use after discharge.¹⁶ To date, there are no published studies that analyze the incidence of opioid-naïve veterans who convert to chronic opioid use after receiving opioids during an acute hospitalization.

In this retrospective analysis, we analyze the incidence of chronic opioid use after administration of opioids in the ICU as well as a variety of risk factors that may influence conversion to chronic opioid use.

Methods

This analysis was a single center, retrospective chart review conducted for patients admitted between July 1, 2017 and December 31, 2017 at the US Department of Veterans Affairs (VA) Michael E. DeBakey VA Medical Center (MEDVAMC) in Houston, Texas. MEDVAMC is a 538-bed academic\teaching hospital serving about 130,000 veterans in Southeast Texas. The hospital has 3 ICUs (medical, cardiovascular, and surgical) and 38 total ICU beds. The study was approved by the Baylor College of Medicine Institutional Review Board and MEDVAMC Research and Development Review Board. Informed consent was not required.

Inclusion criteria consisted of patients aged ≥ 18 years admitted to the ICU in the above-specified time frame, who were administered a continuous infusion of an opioid for at least 12 hours. Patients were excluded if they were not opioid naïve prior to admission, defined as receiving > 30 days of opioids in the prior 12 months. Patients who died during hospital admission, never received an opioid despite having an active order, were hospital-to-hospital transfers, or were still admitted at the time of data collection were excluded from the analysis.

All pertinent data were collected using the VA Computerized Patient Record System (CPRS) and the Critical Care Manager (Picis Clinical Solutions) ICU monitoring application. Critical Care Manager was used to track the time frame, duration, and amounts of opioid infusions administered in the ICU. Patient demographic and preadmission data, including date of birth, age, race, history of substance use/alcohol use disorder (defined as a previous diagnosis) and previous opioid prescriptions within the past year were recorded. For the inpatient admission, the ICU LOS, hospital LOS, primary admission diagnosis, type of opioid medication administered, and total duration and dose of opioid administered were collected. After discharge, opioid medication fill data at 3, 6, and 12 months were collected. This information included names of any outpatient opioids filled, dosage unit, quantity, day supply, and number of refills.

The primary outcome for this study was to determine the incidence of chronic opioid use at 3, 6, and 12 months after discharge, defined as the percentage of patients receiving outpatient opioid prescriptions at each time point. Analyses were conducted to observe the effect of age, race, history of substance use or history of alcohol use (International Classification of Diseases documented diagnosis, 9th edition), ICU type (medical, surgical, or cardiovascular), surgical/nonsurgical admission, ICU LOS, hospital LOS, total time, and amount of opioids administered during admission on risk of conversion to chronic opioid use.

Descriptive statistics were calculated to analyze the incidence of chronic opioid use. Univariate logistic regression analysis, including ORs, 95% CIs, and P values, was conducted to determine the effects of the risk factors noted earlier on chronic opioid use at each time point. A multivariate logistic regression model was performed to assess the effect of multiple independent variables on opioid use at 3, 6, and 12 months. Statistical analysis was performed using StataCorp Stata SE.

Results

During the study period, 330 patients were admitted to the ICU. After applying inclusion/exclusion criteria, 118 patients were included in the final analysis. The most frequent reasons for exclusion from the study were patient death (n = 77), a past history of opioid use (n = 56), and not having received an opioid infusion for at least 12 hours (n = 68). The average age of the patients included was 67 years (Table 1). A total of 14% and 9% of patients, respectively, had a diagnosis of alcohol use disorder or substance use disorder recorded in CPRS. After admission, the most common location for these patients was the surgical ICU (65%). All patients were male. The average hospital LOS was 18.6 days , and the ICU LOS was 8.3 days. The average duration of administration for the opioid (fentanyl) infusion was 63 hours, and the average amount of fentanyl administered to each patient was 57.1 mcg/h.

The incidence of opioid-naïve patients receiving opioids after discharge was 76.3% (n = 90) at 3 months, 19.5% (n = 23) at 6 months and 7.6% (n = 9) at 12 months (Figure). The daily morphine milligram equivalent (MME) of patients prescribed opioids at 3, 6, and 12 months was similar (3 months, 22.7; 6 months, 19.7; 12 months, 20.9). In the univariate regression analysis, several variables were found to be associated with converting to chronic opioid use. Prior history of alcohol use disorder (OR, 0.3; 95% CI, 0.10-0.88; P = .03), ICU type (OR, 3.9; 95% CI, 1.73-8.75; P = .001) and ICU LOS (OR, 0.88; 95% CI, 0.81-0.95; P = .01) had a statistically significant association on opioid use at 3 months. (Table 2). No variables evaluated had a statistically significant effect on chronic opioid use at 6 months, and only age (OR 0.93; 95% CI. 0.87-0.99; P = .02) was statistically significant at 12 months. In the multivariate logistic regression analysis, history of alcohol abuse, admission for surgery, and hospital LOS were significant at 3 months (Table 3).

Discussion

In this single-center analysis conducted at a VA academic hospital of opioid-naïve patients who were administered opioids in the ICU, the incidence of patients subsequently receiving outpatient opioid prescriptions at 12 months after discharge was 7.6%. There also was a decrease in the amount of opioids received by patients (daily MME) after discharge at 3, 6, and 12 months. This trend did not demonstrate the propensity for inpatient opioid use to convert opioid-naïve patients to chronic opioid users.

The most common outpatient opioids prescribed were hydrocodone/acetaminophen, morphine, and tramadol. Logistic regression showed few factors that correlated significantly with opioid use in the long-term (12 month) period. This finding is a deviation from the findings of Yaffe and colleagues who found hospital LOS to be one of the only predictors of long-term opioid use in their population (defined as use at 48 months).¹⁶ One important difference between our study and the Yaffe and colleagues study was that they evaluated all patients who were admitted to the ICU, regardless of the exposure to opioids during their inpatient stay. Consequently, this difference may have resulted in the differences in findings.

Strengths and Limitations

Location was a strength of our study, as this analysis was conducted at an integrated health care system that provides comprehensive inpatient and outpatient care. The VA uses a closed electronic health record, which allowed patients to be followed both in the inpatient and outpatient settings to determine which medications were prescribed at each time. In other health care systems this information would have been difficult to follow as patients often fill outpatient prescriptions at community pharmacies not affiliated with the treating hospital. However, any patient not using a VA prescriber for subsequent opioid prescriptions or patients who received opioids through other sources would not have had their continued opioid use captured. These data may be available in the states prescription monitoring program, but it was not available to query for research at this time.

This study also excluded chronic opioid users, which could have been another confounding factor to account for when analyzing the results. However, the primary objective of the study was to determine the impact of opioids prescribed in the ICU on converting previous opioid-naïve patients to chronic users. Finally, a multivariate logistic regression was incorporated to assess for factors that may predispose certain patients to convert to chronic opioid users. This analysis served to extend the applicability of our study by not only analyzing whether receiving opioids in the ICU contributed to chronic opioid use in the long-term, but also which populations may be at greatest risk. This information can be used in the future to target harm-reduction efforts toward high-risk hospitalized patients.

One limitation of this study was that it was conducted as a retrospective, single-center chart review in Houston, Texas. Because this was not a randomized controlled trial, it is difficult to imply any causation between exposure to opioids in the ICU and chronic use. In addition, because this study was conducted at a single site, the results may not be able to be generalized to other populations. VA populations tend to be elderly and predominantly male, as was reflected by the study population. These factors, along with regional variability in patient characteristics, may limit the generalizability of this study to older male patients located in Southeast Texas or other similar populations. Other limitations of this study also included the small sample size, limited period of follow-up obtained, and that other comorbidity information (pain scores during stay, use of nonopioid pain medications, past history of anxiety or depression, or other acute illnesses or surgeries that may have required opioid therapy during admission) was not collected.

This study was only able to review 118 patients for a follow-up duration of 1 year. In the Yaffe and colleagues study, more than 2,500 patients were followed over 4 years, which provided a more long-term overview of the clinical course of these patients and may be another reason for discrepant findings. However, this study did not actually assess the impact on administration of opioids on the development of chronic opioid use.¹⁶ Finally, the biggest limitation to this study may be the potential for confounding discharge prescriptions. After discharge, patients’ prescriptions were evaluated from discharge to 3 months, in between 3 and 6 months, and between 6 and 12 months for the presence of an opioid prescription. Due to this methodology, any opioid prescription a patient was discharged with was counted in the 3-month time point. Since many patients included in the study were admitted to the surgical ICU (65%), it was logical that they were discharged with opioids after their procedure. While including the immediate postdischarge prescription data was useful for evaluating the decrease in opioid use and incidence over time, it did cause the 3-month time point to appear overly inflated, potentially signaling that at 3 months after discharge many of these patients were still requiring opioid use.

The Society of Critical Care Medicine still recommends opioids as first-line therapy for non-neuropathic pain in the ICU setting.¹⁷ Additionally, postoperative pain can be difficult to manage in the surgical population and is often treated with opioids, though treatment with multimodal pain regimens is becoming more common.¹⁸ It is difficult to imagine that a finding that implicates opioid use in the hospital with conversion to chronic opioid use would prompt a cessation in the use of opioid in these settings, especially in the context of analgosedation related to mechanically ventilated patients. However, it would be plausible to use this knowledge to advocate for opioid-sparing therapies and consideration for weaning individuals at high risk for misuse after discharge from opioid-containing sedation or analgesia regimens in a timelier manner.

Though our findings did not show a clinically relevant increase in chronic opioid users, clinicians can still use this information to encourage targeted education and closer monitoring for those patients deemed as high risk at discharge to prevent unnecessary prolonged opioid use. By having more frequent follow-up in pain clinics, switching patients to nonopioid therapies after discharge, and ensuring high-risk patients are discharged with naloxone rescue kits, it would be possible to drastically reduce the number of potential overdoses for patients who previously required opioid therapy in the ICU.

Conclusion

After discharge, 7.6% of previously opioid-naïve patients who were treated with opioids in the ICU were still receiving prescriptions for opioids at 12 months. These findings did not suggest a clinically significant increase in the incidence of chronic opioid use after inpatient administration of opioids. However, these results prompt the need for larger, prospective, multicenter studies to evaluate the effect on hospitalization on converting to chronic opioid use and a deeper evaluation of other potential risk factors that may be present.

Chronic pain is a worldwide cause of impairment. According to data from the 2016 National Health Interview Survey, an estimated 50 million American adults suffer from chronic pain, with 19.6 million adults suffering from high-impact chronic pain.¹ This phenomenon is particularly prevalent in the older population. More than 25% of adults aged 65 to 74 years reported that they were often in pain in the past 3 months compared with just 10% of those adults between the ages of 18 and 44 years.²

The economic burdens of chronic pain disorders are well known. In 2010, Gaskin and Richard found that chronic pain has far-reaching consequences for the US economy, ranging from direct health care costs to lost productivity. This study estimated additional health care costs at about $300 billion yearly and lost productivity at $300 billion, bringing total annual costs to about $600 billion. This expense is more than heart disease alone ($309 billion), and cancer and diabetes mellitus ($243 billion and $188 billion respectively) combined.³

Opioid medications are powerful and effective pain-reducing agents that are indicated for short-term acute pain or long-term in the management of chronic, severe cancer-related pain.⁴ Although efficacious, use of these medications carries with it the inherent risks of abuse, misuse, addiction, and overdose.⁵ Since 1999, opioid-related overdose deaths have been on the rise. The CDC estimated that > 15,000 deaths were attributable specifically to prescription opioids in 2015.⁶ The estimates had risen to > 17,000 deaths in 2017, with the number increasing since that time.⁷ Cumulatively, the CDC estimates that > 200,000 deaths in the US between 1999 and 2017 are attributed to prescription opioid overdose, clearly marking this trend as a growing nationwide epidemic.⁸

In 2016, Florence and colleagues estimated costs associated with opioid overdose to be just shy of $80 billion in 2013 dollars.⁹ In October 2017, the US Department of Health and Human Services declared the opioid epidemic a public health emergency and committed $900 million to combating the crisis.¹⁰

An abundance of data exist analyzing outpatient prescribing and its impacts on opioid dependence, particularly postoperatively. A study by Brummett and colleagues indicated that the incidence of new persistent opioid use in patients who underwent surgery was 5.9% to 6.5% and did not differ between major and minor surgical procedures. This study concluded that new opioid use could be considered one of the most common complications after elective surgery.¹¹ Similarly, in 2017 Makary and colleagues found that surgeons tend to overprescribe pain medications after procedures; some prescribing as many as 50 to 60 tablets to control pain after simple procedures.¹² This is in stark contrast to pain guideline recommendations of no more than 10 tablets for most standard operative procedures.¹³

Sun and colleagues conducted a retrospective analysis of health care claims data in more than 18 million opioid-naïve patients who did and did not undergo surgery. Seven of the 11 surgical procedures were associated with an increased risk of chronic opioid use. The highest incidence of chronic opioid use in the first postoperative year was for total hip arthroplasty (1.4%, OR 5.10; 95% CI, 1.29-1.53). The study found that the risk factors most associated with chronic opioid use after surgery were male sex, aged > 50 years, and preoperative history of drug abuse, alcohol abuse, or depression, along with benzodiazepine use or antidepressant use.¹⁴ In a 2018 cohort study that evaluated predictors associated with transitioning to incident chronic opioid therapy, 4 factors were identified. These included opioid duration of action (adjusted odds ratio [AOR], 12.28; 95% CI, 8.1-06-18.72), the parent opioid compound (eg, tramadol vs codeine; AOR, 7.26; 95% CI, 5.20-10.13), the presence of conditions that are very likely to cause chronic pain (AOR, 5.47; 95% CI, 3.89-7.68), and drug use disorders (AOR, 4.02; 95% CI, 2.53-6.40).¹⁵

While there has been research into outpatient risk factors and medical practices that may contribute to chronic opioid use, a relative paucity of data exists on the contribution of hospitalization and inpatient opioid use on patient outcomes. A 2014 Canadian study assessed the impact of opioid use in the intensive care unit (ICU) on opioid use after discharge.¹⁶ This study included more than 2,500 patients who were admitted to a Canadian ICU between 2005 and 2008, and then followed after discharge for 48 months to quantify chronic opioid use. Nonopioid users increased from 87.8% in the early post-ICU period to 95.6% at 48 months after discharge. Preadmission chronic opioid use and prolonged hospital length of stay (LOS) were found to be associated with an increased risk of chronic opioid use after discharge.¹⁶ To date, there are no published studies that analyze the incidence of opioid-naïve veterans who convert to chronic opioid use after receiving opioids during an acute hospitalization.

In this retrospective analysis, we analyze the incidence of chronic opioid use after administration of opioids in the ICU as well as a variety of risk factors that may influence conversion to chronic opioid use.

Methods

This analysis was a single center, retrospective chart review conducted for patients admitted between July 1, 2017 and December 31, 2017 at the US Department of Veterans Affairs (VA) Michael E. DeBakey VA Medical Center (MEDVAMC) in Houston, Texas. MEDVAMC is a 538-bed academic\teaching hospital serving about 130,000 veterans in Southeast Texas. The hospital has 3 ICUs (medical, cardiovascular, and surgical) and 38 total ICU beds. The study was approved by the Baylor College of Medicine Institutional Review Board and MEDVAMC Research and Development Review Board. Informed consent was not required.

Inclusion criteria consisted of patients aged ≥ 18 years admitted to the ICU in the above-specified time frame, who were administered a continuous infusion of an opioid for at least 12 hours. Patients were excluded if they were not opioid naïve prior to admission, defined as receiving > 30 days of opioids in the prior 12 months. Patients who died during hospital admission, never received an opioid despite having an active order, were hospital-to-hospital transfers, or were still admitted at the time of data collection were excluded from the analysis.

All pertinent data were collected using the VA Computerized Patient Record System (CPRS) and the Critical Care Manager (Picis Clinical Solutions) ICU monitoring application. Critical Care Manager was used to track the time frame, duration, and amounts of opioid infusions administered in the ICU. Patient demographic and preadmission data, including date of birth, age, race, history of substance use/alcohol use disorder (defined as a previous diagnosis) and previous opioid prescriptions within the past year were recorded. For the inpatient admission, the ICU LOS, hospital LOS, primary admission diagnosis, type of opioid medication administered, and total duration and dose of opioid administered were collected. After discharge, opioid medication fill data at 3, 6, and 12 months were collected. This information included names of any outpatient opioids filled, dosage unit, quantity, day supply, and number of refills.

The primary outcome for this study was to determine the incidence of chronic opioid use at 3, 6, and 12 months after discharge, defined as the percentage of patients receiving outpatient opioid prescriptions at each time point. Analyses were conducted to observe the effect of age, race, history of substance use or history of alcohol use (International Classification of Diseases documented diagnosis, 9th edition), ICU type (medical, surgical, or cardiovascular), surgical/nonsurgical admission, ICU LOS, hospital LOS, total time, and amount of opioids administered during admission on risk of conversion to chronic opioid use.

Descriptive statistics were calculated to analyze the incidence of chronic opioid use. Univariate logistic regression analysis, including ORs, 95% CIs, and P values, was conducted to determine the effects of the risk factors noted earlier on chronic opioid use at each time point. A multivariate logistic regression model was performed to assess the effect of multiple independent variables on opioid use at 3, 6, and 12 months. Statistical analysis was performed using StataCorp Stata SE.

Results

During the study period, 330 patients were admitted to the ICU. After applying inclusion/exclusion criteria, 118 patients were included in the final analysis. The most frequent reasons for exclusion from the study were patient death (n = 77), a past history of opioid use (n = 56), and not having received an opioid infusion for at least 12 hours (n = 68). The average age of the patients included was 67 years (Table 1). A total of 14% and 9% of patients, respectively, had a diagnosis of alcohol use disorder or substance use disorder recorded in CPRS. After admission, the most common location for these patients was the surgical ICU (65%). All patients were male. The average hospital LOS was 18.6 days , and the ICU LOS was 8.3 days. The average duration of administration for the opioid (fentanyl) infusion was 63 hours, and the average amount of fentanyl administered to each patient was 57.1 mcg/h.

The incidence of opioid-naïve patients receiving opioids after discharge was 76.3% (n = 90) at 3 months, 19.5% (n = 23) at 6 months and 7.6% (n = 9) at 12 months (Figure). The daily morphine milligram equivalent (MME) of patients prescribed opioids at 3, 6, and 12 months was similar (3 months, 22.7; 6 months, 19.7; 12 months, 20.9). In the univariate regression analysis, several variables were found to be associated with converting to chronic opioid use. Prior history of alcohol use disorder (OR, 0.3; 95% CI, 0.10-0.88; P = .03), ICU type (OR, 3.9; 95% CI, 1.73-8.75; P = .001) and ICU LOS (OR, 0.88; 95% CI, 0.81-0.95; P = .01) had a statistically significant association on opioid use at 3 months. (Table 2). No variables evaluated had a statistically significant effect on chronic opioid use at 6 months, and only age (OR 0.93; 95% CI. 0.87-0.99; P = .02) was statistically significant at 12 months. In the multivariate logistic regression analysis, history of alcohol abuse, admission for surgery, and hospital LOS were significant at 3 months (Table 3).

Discussion

In this single-center analysis conducted at a VA academic hospital of opioid-naïve patients who were administered opioids in the ICU, the incidence of patients subsequently receiving outpatient opioid prescriptions at 12 months after discharge was 7.6%. There also was a decrease in the amount of opioids received by patients (daily MME) after discharge at 3, 6, and 12 months. This trend did not demonstrate the propensity for inpatient opioid use to convert opioid-naïve patients to chronic opioid users.

The most common outpatient opioids prescribed were hydrocodone/acetaminophen, morphine, and tramadol. Logistic regression showed few factors that correlated significantly with opioid use in the long-term (12 month) period. This finding is a deviation from the findings of Yaffe and colleagues who found hospital LOS to be one of the only predictors of long-term opioid use in their population (defined as use at 48 months).¹⁶ One important difference between our study and the Yaffe and colleagues study was that they evaluated all patients who were admitted to the ICU, regardless of the exposure to opioids during their inpatient stay. Consequently, this difference may have resulted in the differences in findings.

Strengths and Limitations

Location was a strength of our study, as this analysis was conducted at an integrated health care system that provides comprehensive inpatient and outpatient care. The VA uses a closed electronic health record, which allowed patients to be followed both in the inpatient and outpatient settings to determine which medications were prescribed at each time. In other health care systems this information would have been difficult to follow as patients often fill outpatient prescriptions at community pharmacies not affiliated with the treating hospital. However, any patient not using a VA prescriber for subsequent opioid prescriptions or patients who received opioids through other sources would not have had their continued opioid use captured. These data may be available in the states prescription monitoring program, but it was not available to query for research at this time.

This study also excluded chronic opioid users, which could have been another confounding factor to account for when analyzing the results. However, the primary objective of the study was to determine the impact of opioids prescribed in the ICU on converting previous opioid-naïve patients to chronic users. Finally, a multivariate logistic regression was incorporated to assess for factors that may predispose certain patients to convert to chronic opioid users. This analysis served to extend the applicability of our study by not only analyzing whether receiving opioids in the ICU contributed to chronic opioid use in the long-term, but also which populations may be at greatest risk. This information can be used in the future to target harm-reduction efforts toward high-risk hospitalized patients.

One limitation of this study was that it was conducted as a retrospective, single-center chart review in Houston, Texas. Because this was not a randomized controlled trial, it is difficult to imply any causation between exposure to opioids in the ICU and chronic use. In addition, because this study was conducted at a single site, the results may not be able to be generalized to other populations. VA populations tend to be elderly and predominantly male, as was reflected by the study population. These factors, along with regional variability in patient characteristics, may limit the generalizability of this study to older male patients located in Southeast Texas or other similar populations. Other limitations of this study also included the small sample size, limited period of follow-up obtained, and that other comorbidity information (pain scores during stay, use of nonopioid pain medications, past history of anxiety or depression, or other acute illnesses or surgeries that may have required opioid therapy during admission) was not collected.

This study was only able to review 118 patients for a follow-up duration of 1 year. In the Yaffe and colleagues study, more than 2,500 patients were followed over 4 years, which provided a more long-term overview of the clinical course of these patients and may be another reason for discrepant findings. However, this study did not actually assess the impact on administration of opioids on the development of chronic opioid use.¹⁶ Finally, the biggest limitation to this study may be the potential for confounding discharge prescriptions. After discharge, patients’ prescriptions were evaluated from discharge to 3 months, in between 3 and 6 months, and between 6 and 12 months for the presence of an opioid prescription. Due to this methodology, any opioid prescription a patient was discharged with was counted in the 3-month time point. Since many patients included in the study were admitted to the surgical ICU (65%), it was logical that they were discharged with opioids after their procedure. While including the immediate postdischarge prescription data was useful for evaluating the decrease in opioid use and incidence over time, it did cause the 3-month time point to appear overly inflated, potentially signaling that at 3 months after discharge many of these patients were still requiring opioid use.

The Society of Critical Care Medicine still recommends opioids as first-line therapy for non-neuropathic pain in the ICU setting.¹⁷ Additionally, postoperative pain can be difficult to manage in the surgical population and is often treated with opioids, though treatment with multimodal pain regimens is becoming more common.¹⁸ It is difficult to imagine that a finding that implicates opioid use in the hospital with conversion to chronic opioid use would prompt a cessation in the use of opioid in these settings, especially in the context of analgosedation related to mechanically ventilated patients. However, it would be plausible to use this knowledge to advocate for opioid-sparing therapies and consideration for weaning individuals at high risk for misuse after discharge from opioid-containing sedation or analgesia regimens in a timelier manner.

Though our findings did not show a clinically relevant increase in chronic opioid users, clinicians can still use this information to encourage targeted education and closer monitoring for those patients deemed as high risk at discharge to prevent unnecessary prolonged opioid use. By having more frequent follow-up in pain clinics, switching patients to nonopioid therapies after discharge, and ensuring high-risk patients are discharged with naloxone rescue kits, it would be possible to drastically reduce the number of potential overdoses for patients who previously required opioid therapy in the ICU.

Conclusion

After discharge, 7.6% of previously opioid-naïve patients who were treated with opioids in the ICU were still receiving prescriptions for opioids at 12 months. These findings did not suggest a clinically significant increase in the incidence of chronic opioid use after inpatient administration of opioids. However, these results prompt the need for larger, prospective, multicenter studies to evaluate the effect on hospitalization on converting to chronic opioid use and a deeper evaluation of other potential risk factors that may be present.

A 58-year-old white man with a history of alcoholism presented to the emergency department with epigastric and right upper quadrant pain radiating to the back, as well as emesis and anorexia. An elevated lipase of 16,609 U/L (reference range, 31–186 U/L) and pathognomonic abdominal computed tomography (CT) findings (FIGURE 1) led to the diagnosis of acute pancreatitis, for which he was admitted.

Fluid resuscitation and pain management were implemented, and over 3 days his diet was advanced from NPO to clear fluids to a full diet. On the sixth day of hospitalization, the patient developed increasing abdominal pain and worsening leukocytosis (white blood cell count, 16.6–22 K/mcL [reference range, 4.5–11 K/mcL]). Repeat CT and blood cultures were obtained, and the patient was started on intravenous meropenem 1 g every 8 hours for presumed necrotizing pancreatitis. The next day he developed acutely tender red to pink patches and nodules on his shins and medial lower legs (FIGURE 2).

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

Pancreatic panniculitis, or enzymatic panniculitis, is a rare necrotizing subcutaneous inflammatory process that occurs in 2% to 3% of cases of pancreatic disease.¹ It is associated with acute and chronic pancreatitis, pancreatic carcinoma (typically pancreatic acinar type), and less commonly, with pancreatic anomalies such as pancreatic divisum.^1,2

It’s theorized that the systemic release of trypsin from pancreatic cell destruction causes increased capillary permeability and subsequent escape of lipase from the circulation into the subcutaneous fat. This causes fat necrosis, saponification, and inflammation.^3,4 Pancreatic panniculitis is demonstrated histologically as hollowed-out adipocytes with granular basophilic cytoplasm and displaced or absent nuclei—aptly named “ghostlike” adipocytes.^3-6

Painful, erythematous nodules most commonly present on the distal lower extremities. Nodules may be found over the shins, posterior calves, and periarticular skin. Rarely, nodules may occur on the buttocks, abdomen, or intramedullary bone.⁷ In severe cases, nodules spontaneously may ulcerate and drain an oily brown, viscous material formed from necrotic adipocytes.¹

Timing of the eruption of skin lesions is varied and may even precede abdominal pain. Lesions can involute and regress several weeks after the underlying etiology improves. With pancreatic carcinoma, there is a greater likelihood of persistence, atypical locations of involvement, ulcerations, and recurrences.⁷

The histologic features of pancreatic panniculitis and the assessment of the subcutaneous fat are paramount in diagnosis. A deep punch biopsy or incisional biopsy is necessary to reliably reach the depth of the subcutaneous tissue. In our patient, a deep punch biopsy from the lateral calf was performed at the suggestion of Dermatology, and histopathology revealed necrosis of fat lobules with calcium soap around necrotic lipocytes, consistent with pancreatic panniculitis (FIGURE 3).

Continue to: Differential was complicated by antibiotic use

The differential diagnosis was broad due to the confounding factors of recent antibiotic use and worsening pancreatitis.

Cellulitis may present as a red patch and is common on the lower legs; it often is associated with skin pathogens including Staphylococcus and Streptococcus. Usually, symptoms are unilateral and associated with warmth to the touch, expanding borders, leukocytosis, and systemic symptoms.

Vasculitis, which is an inflammation of various sized vessels through immunologic or infectious processes, often manifests on the lower legs. The characteristic sign of small vessel vasculitis is nonblanching purpura or petechiae. There often is a preceding illness or medication that triggers immunoglobulin proliferation and off-target inflammation of the vessels. Associated symptoms include pain and pruritus.

Drug eruptions may present as red patches on the skin. Often the patches are scaly and red and have more widespread distribution than the lower legs. A history of exposure is important, but common inciting drugs include nonsteroidal anti-inflammatory drugs that may be used only occasionally and are challenging to elicit in the history. Our patient did have known drug changes (ie, the introduction of meropenem) while hospitalized, but the morphology was not consistent with this diagnosis.

Treatment is directed to underlying disease

Treatment of pancreatic panniculitis primarily is supportive and directed toward treating the underlying pancreatic disease. Depending upon the underlying pancreatic diagnosis, surgical correction of anatomic or ductal anomalies or pseudocysts may lead to resolution of panniculitis.^3,7,8

Continue to: In this case

In this case, our patient had already received fluid resuscitation and pain management, and his diet had been advanced. In addition, his antibiotics were changed to exclude drug eruption as a cause. Over the course of a week, our patient saw a reduction in his pain level and an improvement in the appearance of his legs (FIGURE 4).

His pancreatitis, however, continued to persist and resist increases in his diet. He ultimately required transfer to a tertiary care center for consideration of interventional options including stenting. The patient ultimately recovered, after stenting of the main pancreatic duct, and was discharged home.

CORRESPONDENCE
Jonathan Karnes, MD, 6 East Chestnut Street, Augusta, ME 04330; [email protected]

A 58-year-old white man with a history of alcoholism presented to the emergency department with epigastric and right upper quadrant pain radiating to the back, as well as emesis and anorexia. An elevated lipase of 16,609 U/L (reference range, 31–186 U/L) and pathognomonic abdominal computed tomography (CT) findings (FIGURE 1) led to the diagnosis of acute pancreatitis, for which he was admitted.

Fluid resuscitation and pain management were implemented, and over 3 days his diet was advanced from NPO to clear fluids to a full diet. On the sixth day of hospitalization, the patient developed increasing abdominal pain and worsening leukocytosis (white blood cell count, 16.6–22 K/mcL [reference range, 4.5–11 K/mcL]). Repeat CT and blood cultures were obtained, and the patient was started on intravenous meropenem 1 g every 8 hours for presumed necrotizing pancreatitis. The next day he developed acutely tender red to pink patches and nodules on his shins and medial lower legs (FIGURE 2).

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

Pancreatic panniculitis, or enzymatic panniculitis, is a rare necrotizing subcutaneous inflammatory process that occurs in 2% to 3% of cases of pancreatic disease.¹ It is associated with acute and chronic pancreatitis, pancreatic carcinoma (typically pancreatic acinar type), and less commonly, with pancreatic anomalies such as pancreatic divisum.^1,2

It’s theorized that the systemic release of trypsin from pancreatic cell destruction causes increased capillary permeability and subsequent escape of lipase from the circulation into the subcutaneous fat. This causes fat necrosis, saponification, and inflammation.^3,4 Pancreatic panniculitis is demonstrated histologically as hollowed-out adipocytes with granular basophilic cytoplasm and displaced or absent nuclei—aptly named “ghostlike” adipocytes.^3-6

Painful, erythematous nodules most commonly present on the distal lower extremities. Nodules may be found over the shins, posterior calves, and periarticular skin. Rarely, nodules may occur on the buttocks, abdomen, or intramedullary bone.⁷ In severe cases, nodules spontaneously may ulcerate and drain an oily brown, viscous material formed from necrotic adipocytes.¹

Timing of the eruption of skin lesions is varied and may even precede abdominal pain. Lesions can involute and regress several weeks after the underlying etiology improves. With pancreatic carcinoma, there is a greater likelihood of persistence, atypical locations of involvement, ulcerations, and recurrences.⁷

The histologic features of pancreatic panniculitis and the assessment of the subcutaneous fat are paramount in diagnosis. A deep punch biopsy or incisional biopsy is necessary to reliably reach the depth of the subcutaneous tissue. In our patient, a deep punch biopsy from the lateral calf was performed at the suggestion of Dermatology, and histopathology revealed necrosis of fat lobules with calcium soap around necrotic lipocytes, consistent with pancreatic panniculitis (FIGURE 3).

Continue to: Differential was complicated by antibiotic use

The differential diagnosis was broad due to the confounding factors of recent antibiotic use and worsening pancreatitis.

Cellulitis may present as a red patch and is common on the lower legs; it often is associated with skin pathogens including Staphylococcus and Streptococcus. Usually, symptoms are unilateral and associated with warmth to the touch, expanding borders, leukocytosis, and systemic symptoms.

Vasculitis, which is an inflammation of various sized vessels through immunologic or infectious processes, often manifests on the lower legs. The characteristic sign of small vessel vasculitis is nonblanching purpura or petechiae. There often is a preceding illness or medication that triggers immunoglobulin proliferation and off-target inflammation of the vessels. Associated symptoms include pain and pruritus.

Drug eruptions may present as red patches on the skin. Often the patches are scaly and red and have more widespread distribution than the lower legs. A history of exposure is important, but common inciting drugs include nonsteroidal anti-inflammatory drugs that may be used only occasionally and are challenging to elicit in the history. Our patient did have known drug changes (ie, the introduction of meropenem) while hospitalized, but the morphology was not consistent with this diagnosis.

Treatment is directed to underlying disease

Treatment of pancreatic panniculitis primarily is supportive and directed toward treating the underlying pancreatic disease. Depending upon the underlying pancreatic diagnosis, surgical correction of anatomic or ductal anomalies or pseudocysts may lead to resolution of panniculitis.^3,7,8

Continue to: In this case

In this case, our patient had already received fluid resuscitation and pain management, and his diet had been advanced. In addition, his antibiotics were changed to exclude drug eruption as a cause. Over the course of a week, our patient saw a reduction in his pain level and an improvement in the appearance of his legs (FIGURE 4).

His pancreatitis, however, continued to persist and resist increases in his diet. He ultimately required transfer to a tertiary care center for consideration of interventional options including stenting. The patient ultimately recovered, after stenting of the main pancreatic duct, and was discharged home.

CORRESPONDENCE
Jonathan Karnes, MD, 6 East Chestnut Street, Augusta, ME 04330; [email protected]

A 58-year-old white man with a history of alcoholism presented to the emergency department with epigastric and right upper quadrant pain radiating to the back, as well as emesis and anorexia. An elevated lipase of 16,609 U/L (reference range, 31–186 U/L) and pathognomonic abdominal computed tomography (CT) findings (FIGURE 1) led to the diagnosis of acute pancreatitis, for which he was admitted.

Fluid resuscitation and pain management were implemented, and over 3 days his diet was advanced from NPO to clear fluids to a full diet. On the sixth day of hospitalization, the patient developed increasing abdominal pain and worsening leukocytosis (white blood cell count, 16.6–22 K/mcL [reference range, 4.5–11 K/mcL]). Repeat CT and blood cultures were obtained, and the patient was started on intravenous meropenem 1 g every 8 hours for presumed necrotizing pancreatitis. The next day he developed acutely tender red to pink patches and nodules on his shins and medial lower legs (FIGURE 2).

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

Pancreatic panniculitis, or enzymatic panniculitis, is a rare necrotizing subcutaneous inflammatory process that occurs in 2% to 3% of cases of pancreatic disease.¹ It is associated with acute and chronic pancreatitis, pancreatic carcinoma (typically pancreatic acinar type), and less commonly, with pancreatic anomalies such as pancreatic divisum.^1,2

It’s theorized that the systemic release of trypsin from pancreatic cell destruction causes increased capillary permeability and subsequent escape of lipase from the circulation into the subcutaneous fat. This causes fat necrosis, saponification, and inflammation.^3,4 Pancreatic panniculitis is demonstrated histologically as hollowed-out adipocytes with granular basophilic cytoplasm and displaced or absent nuclei—aptly named “ghostlike” adipocytes.^3-6

Painful, erythematous nodules most commonly present on the distal lower extremities. Nodules may be found over the shins, posterior calves, and periarticular skin. Rarely, nodules may occur on the buttocks, abdomen, or intramedullary bone.⁷ In severe cases, nodules spontaneously may ulcerate and drain an oily brown, viscous material formed from necrotic adipocytes.¹

Timing of the eruption of skin lesions is varied and may even precede abdominal pain. Lesions can involute and regress several weeks after the underlying etiology improves. With pancreatic carcinoma, there is a greater likelihood of persistence, atypical locations of involvement, ulcerations, and recurrences.⁷

The histologic features of pancreatic panniculitis and the assessment of the subcutaneous fat are paramount in diagnosis. A deep punch biopsy or incisional biopsy is necessary to reliably reach the depth of the subcutaneous tissue. In our patient, a deep punch biopsy from the lateral calf was performed at the suggestion of Dermatology, and histopathology revealed necrosis of fat lobules with calcium soap around necrotic lipocytes, consistent with pancreatic panniculitis (FIGURE 3).

Continue to: Differential was complicated by antibiotic use

The differential diagnosis was broad due to the confounding factors of recent antibiotic use and worsening pancreatitis.

Cellulitis may present as a red patch and is common on the lower legs; it often is associated with skin pathogens including Staphylococcus and Streptococcus. Usually, symptoms are unilateral and associated with warmth to the touch, expanding borders, leukocytosis, and systemic symptoms.

Vasculitis, which is an inflammation of various sized vessels through immunologic or infectious processes, often manifests on the lower legs. The characteristic sign of small vessel vasculitis is nonblanching purpura or petechiae. There often is a preceding illness or medication that triggers immunoglobulin proliferation and off-target inflammation of the vessels. Associated symptoms include pain and pruritus.

Drug eruptions may present as red patches on the skin. Often the patches are scaly and red and have more widespread distribution than the lower legs. A history of exposure is important, but common inciting drugs include nonsteroidal anti-inflammatory drugs that may be used only occasionally and are challenging to elicit in the history. Our patient did have known drug changes (ie, the introduction of meropenem) while hospitalized, but the morphology was not consistent with this diagnosis.

Treatment is directed to underlying disease

Treatment of pancreatic panniculitis primarily is supportive and directed toward treating the underlying pancreatic disease. Depending upon the underlying pancreatic diagnosis, surgical correction of anatomic or ductal anomalies or pseudocysts may lead to resolution of panniculitis.^3,7,8

Continue to: In this case

In this case, our patient had already received fluid resuscitation and pain management, and his diet had been advanced. In addition, his antibiotics were changed to exclude drug eruption as a cause. Over the course of a week, our patient saw a reduction in his pain level and an improvement in the appearance of his legs (FIGURE 4).

His pancreatitis, however, continued to persist and resist increases in his diet. He ultimately required transfer to a tertiary care center for consideration of interventional options including stenting. The patient ultimately recovered, after stenting of the main pancreatic duct, and was discharged home.

CORRESPONDENCE
Jonathan Karnes, MD, 6 East Chestnut Street, Augusta, ME 04330; [email protected]

THE CASE

A 64-year-old woman with a history of late-onset type 1 diabetes mellitus, Hashimoto thyroiditis, and scoliosis presented to the sports medicine clinic with acute-onset, sharp, nonradiating right lower back pain that began when she bent forward to apply lotion. At presentation, she denied fever, chills, numbness, tingling, aggravation of pain with movement, weakness, and incontinence. Her neuromuscular examination was unremarkable except for left-side paraspinal tenderness. She was prescribed cyclobenzaprine for symptomatic relief.

Two days later, she was seen for worsening pain. Her physical exam was unchanged. She was prescribed tramadol and advised to start physical therapy gradually. As the day ­progressed, however, she developed anterior thigh sensory loss, which gradually extended distally.

The following day, she was brought to the emergency department with severe left-side weakness without urinary incontinence. Her mental status and cranial nerve exams were normal. On examination, strength of the iliopsoas and quadriceps was 1/5 bilaterally, and of the peroneal tendon and gastrocnemius, 3/5 bilaterally. Reflexes of triceps, biceps, knee, and Achilles tendon were symmetric and 3+ with bilateral clonus of the ankle. The Babinski sign was positive bilaterally. The patient had diminished pain sensation bilaterally, extending down from the T11 dermatome (left more than right side) with diminished vibration sensation at the left ankle. Her perianal sensation, bilateral temperature sensation, and cerebellar examination were normal.

Magnetic resonance imaging (MRI) without contrast of the lumbar spine demonstrated ischemia findings corresponding to T12-L1. Degenerative changes from L1-S1 were noted, with multiple osteophytes impinging on the neural foramina without cord compression.

THE DIAGNOSIS

The initial presentation was consistent with mechanical low back pain with signs of anterior spinal artery infarction and medial lemniscus pathway involvement 48 hours after initial presentation. Spinal cord infarction occurs more commonly in women and in the young than does cerebral infarction,¹ with better reemployment rates.^1,2 Similar to other strokes, long-term prognosis is primarily determined by the initial severity of motor impairment, which is linked to long-term immobility and need for bladder catheterization.³

Neurogenic pain developing years after spinal cord infarction is most often observed in anterior spinal artery infarction⁴ without functional limitations.

Initial treatment. Our patient was started on aspirin 325 mg/d and clopidogrel 75 mg/d. Her mean arterial blood pressure was maintained above 80 mm Hg. Computed tomography angiography of the abdomen and pelvis was negative for aortic dissection. Lumbar puncture for cerebrospinal fluid analysis was unremarkable. Results of antineutrophil cytoplasmic antibody testing, antinuclear antibody testing, a hepatitis panel, and an antiphospholipid panel were all negative. The patient was started on IV steroids with a plan for gradual tapering. The neurosurgical team agreed with medical management.

Continue to: DISCUSSION

Possible etiologies for acute spinal cord infarction include spinal cord ischemia from compression of the vessels, fibrocartilaginous embolism, and arterial thrombosis or atherosclerosis, especially in patients with diabetes.⁵

The majority (86%) of spinal strokes are due to spontaneous occlusion of the vessels with no identifiable cause; much less frequently (9% of cases), hemorrhage is the causative factor.¹ A retrospective study demonstrated that 10 of 27 patients with spinal stroke had an anterior spinal infarct. Of those 10 patients, 6 reported a mechanical triggering movement (similar to this case), indicating potential compression of the radicular arteries due to said movement.⁴

Fibrocartilaginous embolism (FCE) is worth considering as a possible cause, because it accounts for 5.5% of all cases of acute spinal cord infarction.³ FCE is thought to arise after a precipitating event such as minor trauma, heavy lifting, physical exertion, or Valsalva maneuver causing embolization of the fragments of nucleus pulposus to the arterial system. In a case series of 8 patients, 2 had possible FCE with precipitating events occurring within the prior 24 hours. This was also demonstrated in another case series⁶ in which 7 of 9 patients had precipitating events.

Although FCE can only definitively be diagnosed postmortem, the researchers⁶ proposed clinical criteria for its diagnosis in living patients, based on 40 postmortem and 11 suspected antemortem cases of FCE. These criteria include a rapid evolution of symptoms consistent with vascular etiology, with or without preceding minor trauma or Valsalva maneuver; MRI changes consistent with ischemic myelopathy, with or without evidence of disc herniation; and no more than 2 vascular risk factors.

Our patient had no trauma (although there was a triggering movement), no signs of disc herniation, and 2 risk factors (> 60 years and diabetes mellitus). Also, a neurologically symptom-free interval between the painful movement and the onset of neurologic manifestations in our case parallels the clinical picture of FCE.

Continue to: The role of factor V Leiden (FVL) mutation

The role of factor V Leiden (FVL) mutation in arterial thrombosis is questionable. Previous reports demonstrate a risk for venous thrombosis 7 to 10 times higher with heterozygous FVL mutation and 100 times higher with homozygous mutation, with a less established role in arterial thrombosis.⁷ A retrospective Turkish study compared the incidence of FVL mutation in patients with arterial thrombosis vs healthy subjects; incidence was significantly higher in female patients than female controls (37.5% vs. 2%).⁷ A meta-analysis of published studies showed an association between arterial ischemic events and FVL mutation to be modest, with an odds ratio of 1.21 (95% CI, 0.99-1.49).⁸

The majority of spinal strokes are due to spontaneous occlusion of the vessels with no identifiable cause.

In contrast, a 3.4-year longitudinal health study of patients ages 65 and older found no significant difference in the occurrence of myocardial infarction, transient ischemic attack, stroke, or angina for more than 5000 patients with heterozygous FVL mutation compared to fewer than 500 controls.⁹ The case patient’s clinical course did not fit a thrombotic clinical picture.

Evaluating for “red flags” is crucial in any case of low back pain to exclude serious pathologies. Red flag symptoms include signs of myelopathy, signs of infection, history of trauma with focal tenderness to palpation, and steroid or anticoagulant use (to rule out medication adverse effects).¹⁰ Our patient lacked these classical signs, but she did have subjective pain out of proportion to the clinical exam findings.

Of note: The above red flags for low back pain are all based on expert opinion,¹¹ and the positive predictive value of a red flag is always low because of the low prevalence of serious spinal pathologies.¹²

Striking a proper balance. This case emphasizes the necessity to keep uncommon causes—such as nontraumatic spinal stroke, which has a prevalence of about 5% to 8% of all acute myelopathies—in the differential diagnosis.³

Continue to: We recommend watchful...

We recommend watchful waiting coupled with communication with the patient regarding monitoring for changes in symptoms over time.¹¹ Any changes in symptoms concerning for underlying spinal cord injury indicate necessity for transfer to a tertiary care center (if possible), along with immediate evaluation with imaging—including computed tomography angiography of the abdomen to rule out aortic dissection (1%-2% of all spinal cord infarcts), followed by a specialist consultation based on the findings.³

Our patient

Our patient was discharged to rehabilitation on hospital Day 5, after progressive return of lower extremity strength. At the 2-month follow-up visit, she demonstrated grade 4+ strength throughout her lower extremities bilaterally. Weakness was predominant at the hip flexors and ankle dorsiflexors, which was consistent with her status at discharge. She had burning pain in the distribution of the L1 dermatome that responded to ibuprofen.

Hypercoagulability work-up was positive for heterozygous FVL mutation without any previous history of venous thromboembolic disease. She was continued on aspirin 325 mg/d, as per American College of Chest Physicians antithrombotic guidelines.¹³

One year later, our patient underwent a follow-up MRI of the thoracic spine, which showed an “owl’s eye” hyperintensity in the anterior cord (FIGURE), a sign that’s often seen in bilateral spinal cord infarction.¹⁴ At 18-month follow-up, the patient had regained her baseline strength with persistent hyperreflexia.

THE TAKEAWAY

Spinal stroke is rare, but a missed diagnosis and lack of treatment can result in long-term morbidity. Therefore, it is prudent to consider this diagnosis in the differential—especially when the patient’s subjective back pain is out of proportion to the clinical examination findings.

CORRESPONDENCE
Srikanth Nithyanandam, MBBS, MS, University of Kentucky Family and Community Medicine, 2195 Harrodsburg Road, Suite 125, Lexington, KY 40504-3504; [email protected].

THE CASE

A 64-year-old woman with a history of late-onset type 1 diabetes mellitus, Hashimoto thyroiditis, and scoliosis presented to the sports medicine clinic with acute-onset, sharp, nonradiating right lower back pain that began when she bent forward to apply lotion. At presentation, she denied fever, chills, numbness, tingling, aggravation of pain with movement, weakness, and incontinence. Her neuromuscular examination was unremarkable except for left-side paraspinal tenderness. She was prescribed cyclobenzaprine for symptomatic relief.

Two days later, she was seen for worsening pain. Her physical exam was unchanged. She was prescribed tramadol and advised to start physical therapy gradually. As the day ­progressed, however, she developed anterior thigh sensory loss, which gradually extended distally.

The following day, she was brought to the emergency department with severe left-side weakness without urinary incontinence. Her mental status and cranial nerve exams were normal. On examination, strength of the iliopsoas and quadriceps was 1/5 bilaterally, and of the peroneal tendon and gastrocnemius, 3/5 bilaterally. Reflexes of triceps, biceps, knee, and Achilles tendon were symmetric and 3+ with bilateral clonus of the ankle. The Babinski sign was positive bilaterally. The patient had diminished pain sensation bilaterally, extending down from the T11 dermatome (left more than right side) with diminished vibration sensation at the left ankle. Her perianal sensation, bilateral temperature sensation, and cerebellar examination were normal.

Magnetic resonance imaging (MRI) without contrast of the lumbar spine demonstrated ischemia findings corresponding to T12-L1. Degenerative changes from L1-S1 were noted, with multiple osteophytes impinging on the neural foramina without cord compression.

THE DIAGNOSIS

The initial presentation was consistent with mechanical low back pain with signs of anterior spinal artery infarction and medial lemniscus pathway involvement 48 hours after initial presentation. Spinal cord infarction occurs more commonly in women and in the young than does cerebral infarction,¹ with better reemployment rates.^1,2 Similar to other strokes, long-term prognosis is primarily determined by the initial severity of motor impairment, which is linked to long-term immobility and need for bladder catheterization.³

Neurogenic pain developing years after spinal cord infarction is most often observed in anterior spinal artery infarction⁴ without functional limitations.

Initial treatment. Our patient was started on aspirin 325 mg/d and clopidogrel 75 mg/d. Her mean arterial blood pressure was maintained above 80 mm Hg. Computed tomography angiography of the abdomen and pelvis was negative for aortic dissection. Lumbar puncture for cerebrospinal fluid analysis was unremarkable. Results of antineutrophil cytoplasmic antibody testing, antinuclear antibody testing, a hepatitis panel, and an antiphospholipid panel were all negative. The patient was started on IV steroids with a plan for gradual tapering. The neurosurgical team agreed with medical management.

Continue to: DISCUSSION

Possible etiologies for acute spinal cord infarction include spinal cord ischemia from compression of the vessels, fibrocartilaginous embolism, and arterial thrombosis or atherosclerosis, especially in patients with diabetes.⁵

The majority (86%) of spinal strokes are due to spontaneous occlusion of the vessels with no identifiable cause; much less frequently (9% of cases), hemorrhage is the causative factor.¹ A retrospective study demonstrated that 10 of 27 patients with spinal stroke had an anterior spinal infarct. Of those 10 patients, 6 reported a mechanical triggering movement (similar to this case), indicating potential compression of the radicular arteries due to said movement.⁴

Fibrocartilaginous embolism (FCE) is worth considering as a possible cause, because it accounts for 5.5% of all cases of acute spinal cord infarction.³ FCE is thought to arise after a precipitating event such as minor trauma, heavy lifting, physical exertion, or Valsalva maneuver causing embolization of the fragments of nucleus pulposus to the arterial system. In a case series of 8 patients, 2 had possible FCE with precipitating events occurring within the prior 24 hours. This was also demonstrated in another case series⁶ in which 7 of 9 patients had precipitating events.

Although FCE can only definitively be diagnosed postmortem, the researchers⁶ proposed clinical criteria for its diagnosis in living patients, based on 40 postmortem and 11 suspected antemortem cases of FCE. These criteria include a rapid evolution of symptoms consistent with vascular etiology, with or without preceding minor trauma or Valsalva maneuver; MRI changes consistent with ischemic myelopathy, with or without evidence of disc herniation; and no more than 2 vascular risk factors.

Our patient had no trauma (although there was a triggering movement), no signs of disc herniation, and 2 risk factors (> 60 years and diabetes mellitus). Also, a neurologically symptom-free interval between the painful movement and the onset of neurologic manifestations in our case parallels the clinical picture of FCE.

Continue to: The role of factor V Leiden (FVL) mutation

The role of factor V Leiden (FVL) mutation in arterial thrombosis is questionable. Previous reports demonstrate a risk for venous thrombosis 7 to 10 times higher with heterozygous FVL mutation and 100 times higher with homozygous mutation, with a less established role in arterial thrombosis.⁷ A retrospective Turkish study compared the incidence of FVL mutation in patients with arterial thrombosis vs healthy subjects; incidence was significantly higher in female patients than female controls (37.5% vs. 2%).⁷ A meta-analysis of published studies showed an association between arterial ischemic events and FVL mutation to be modest, with an odds ratio of 1.21 (95% CI, 0.99-1.49).⁸

The majority of spinal strokes are due to spontaneous occlusion of the vessels with no identifiable cause.

In contrast, a 3.4-year longitudinal health study of patients ages 65 and older found no significant difference in the occurrence of myocardial infarction, transient ischemic attack, stroke, or angina for more than 5000 patients with heterozygous FVL mutation compared to fewer than 500 controls.⁹ The case patient’s clinical course did not fit a thrombotic clinical picture.

Evaluating for “red flags” is crucial in any case of low back pain to exclude serious pathologies. Red flag symptoms include signs of myelopathy, signs of infection, history of trauma with focal tenderness to palpation, and steroid or anticoagulant use (to rule out medication adverse effects).¹⁰ Our patient lacked these classical signs, but she did have subjective pain out of proportion to the clinical exam findings.

Of note: The above red flags for low back pain are all based on expert opinion,¹¹ and the positive predictive value of a red flag is always low because of the low prevalence of serious spinal pathologies.¹²

Striking a proper balance. This case emphasizes the necessity to keep uncommon causes—such as nontraumatic spinal stroke, which has a prevalence of about 5% to 8% of all acute myelopathies—in the differential diagnosis.³

Continue to: We recommend watchful...

We recommend watchful waiting coupled with communication with the patient regarding monitoring for changes in symptoms over time.¹¹ Any changes in symptoms concerning for underlying spinal cord injury indicate necessity for transfer to a tertiary care center (if possible), along with immediate evaluation with imaging—including computed tomography angiography of the abdomen to rule out aortic dissection (1%-2% of all spinal cord infarcts), followed by a specialist consultation based on the findings.³

Our patient

Our patient was discharged to rehabilitation on hospital Day 5, after progressive return of lower extremity strength. At the 2-month follow-up visit, she demonstrated grade 4+ strength throughout her lower extremities bilaterally. Weakness was predominant at the hip flexors and ankle dorsiflexors, which was consistent with her status at discharge. She had burning pain in the distribution of the L1 dermatome that responded to ibuprofen.

Hypercoagulability work-up was positive for heterozygous FVL mutation without any previous history of venous thromboembolic disease. She was continued on aspirin 325 mg/d, as per American College of Chest Physicians antithrombotic guidelines.¹³

One year later, our patient underwent a follow-up MRI of the thoracic spine, which showed an “owl’s eye” hyperintensity in the anterior cord (FIGURE), a sign that’s often seen in bilateral spinal cord infarction.¹⁴ At 18-month follow-up, the patient had regained her baseline strength with persistent hyperreflexia.

THE TAKEAWAY

Spinal stroke is rare, but a missed diagnosis and lack of treatment can result in long-term morbidity. Therefore, it is prudent to consider this diagnosis in the differential—especially when the patient’s subjective back pain is out of proportion to the clinical examination findings.

CORRESPONDENCE
Srikanth Nithyanandam, MBBS, MS, University of Kentucky Family and Community Medicine, 2195 Harrodsburg Road, Suite 125, Lexington, KY 40504-3504; [email protected].

THE CASE

A 64-year-old woman with a history of late-onset type 1 diabetes mellitus, Hashimoto thyroiditis, and scoliosis presented to the sports medicine clinic with acute-onset, sharp, nonradiating right lower back pain that began when she bent forward to apply lotion. At presentation, she denied fever, chills, numbness, tingling, aggravation of pain with movement, weakness, and incontinence. Her neuromuscular examination was unremarkable except for left-side paraspinal tenderness. She was prescribed cyclobenzaprine for symptomatic relief.

Two days later, she was seen for worsening pain. Her physical exam was unchanged. She was prescribed tramadol and advised to start physical therapy gradually. As the day ­progressed, however, she developed anterior thigh sensory loss, which gradually extended distally.

The following day, she was brought to the emergency department with severe left-side weakness without urinary incontinence. Her mental status and cranial nerve exams were normal. On examination, strength of the iliopsoas and quadriceps was 1/5 bilaterally, and of the peroneal tendon and gastrocnemius, 3/5 bilaterally. Reflexes of triceps, biceps, knee, and Achilles tendon were symmetric and 3+ with bilateral clonus of the ankle. The Babinski sign was positive bilaterally. The patient had diminished pain sensation bilaterally, extending down from the T11 dermatome (left more than right side) with diminished vibration sensation at the left ankle. Her perianal sensation, bilateral temperature sensation, and cerebellar examination were normal.

Magnetic resonance imaging (MRI) without contrast of the lumbar spine demonstrated ischemia findings corresponding to T12-L1. Degenerative changes from L1-S1 were noted, with multiple osteophytes impinging on the neural foramina without cord compression.

THE DIAGNOSIS

The initial presentation was consistent with mechanical low back pain with signs of anterior spinal artery infarction and medial lemniscus pathway involvement 48 hours after initial presentation. Spinal cord infarction occurs more commonly in women and in the young than does cerebral infarction,¹ with better reemployment rates.^1,2 Similar to other strokes, long-term prognosis is primarily determined by the initial severity of motor impairment, which is linked to long-term immobility and need for bladder catheterization.³

Neurogenic pain developing years after spinal cord infarction is most often observed in anterior spinal artery infarction⁴ without functional limitations.

Initial treatment. Our patient was started on aspirin 325 mg/d and clopidogrel 75 mg/d. Her mean arterial blood pressure was maintained above 80 mm Hg. Computed tomography angiography of the abdomen and pelvis was negative for aortic dissection. Lumbar puncture for cerebrospinal fluid analysis was unremarkable. Results of antineutrophil cytoplasmic antibody testing, antinuclear antibody testing, a hepatitis panel, and an antiphospholipid panel were all negative. The patient was started on IV steroids with a plan for gradual tapering. The neurosurgical team agreed with medical management.

Continue to: DISCUSSION

Possible etiologies for acute spinal cord infarction include spinal cord ischemia from compression of the vessels, fibrocartilaginous embolism, and arterial thrombosis or atherosclerosis, especially in patients with diabetes.⁵

The majority (86%) of spinal strokes are due to spontaneous occlusion of the vessels with no identifiable cause; much less frequently (9% of cases), hemorrhage is the causative factor.¹ A retrospective study demonstrated that 10 of 27 patients with spinal stroke had an anterior spinal infarct. Of those 10 patients, 6 reported a mechanical triggering movement (similar to this case), indicating potential compression of the radicular arteries due to said movement.⁴

Fibrocartilaginous embolism (FCE) is worth considering as a possible cause, because it accounts for 5.5% of all cases of acute spinal cord infarction.³ FCE is thought to arise after a precipitating event such as minor trauma, heavy lifting, physical exertion, or Valsalva maneuver causing embolization of the fragments of nucleus pulposus to the arterial system. In a case series of 8 patients, 2 had possible FCE with precipitating events occurring within the prior 24 hours. This was also demonstrated in another case series⁶ in which 7 of 9 patients had precipitating events.

Although FCE can only definitively be diagnosed postmortem, the researchers⁶ proposed clinical criteria for its diagnosis in living patients, based on 40 postmortem and 11 suspected antemortem cases of FCE. These criteria include a rapid evolution of symptoms consistent with vascular etiology, with or without preceding minor trauma or Valsalva maneuver; MRI changes consistent with ischemic myelopathy, with or without evidence of disc herniation; and no more than 2 vascular risk factors.

Our patient had no trauma (although there was a triggering movement), no signs of disc herniation, and 2 risk factors (> 60 years and diabetes mellitus). Also, a neurologically symptom-free interval between the painful movement and the onset of neurologic manifestations in our case parallels the clinical picture of FCE.

Continue to: The role of factor V Leiden (FVL) mutation

The role of factor V Leiden (FVL) mutation in arterial thrombosis is questionable. Previous reports demonstrate a risk for venous thrombosis 7 to 10 times higher with heterozygous FVL mutation and 100 times higher with homozygous mutation, with a less established role in arterial thrombosis.⁷ A retrospective Turkish study compared the incidence of FVL mutation in patients with arterial thrombosis vs healthy subjects; incidence was significantly higher in female patients than female controls (37.5% vs. 2%).⁷ A meta-analysis of published studies showed an association between arterial ischemic events and FVL mutation to be modest, with an odds ratio of 1.21 (95% CI, 0.99-1.49).⁸

The majority of spinal strokes are due to spontaneous occlusion of the vessels with no identifiable cause.

In contrast, a 3.4-year longitudinal health study of patients ages 65 and older found no significant difference in the occurrence of myocardial infarction, transient ischemic attack, stroke, or angina for more than 5000 patients with heterozygous FVL mutation compared to fewer than 500 controls.⁹ The case patient’s clinical course did not fit a thrombotic clinical picture.

Evaluating for “red flags” is crucial in any case of low back pain to exclude serious pathologies. Red flag symptoms include signs of myelopathy, signs of infection, history of trauma with focal tenderness to palpation, and steroid or anticoagulant use (to rule out medication adverse effects).¹⁰ Our patient lacked these classical signs, but she did have subjective pain out of proportion to the clinical exam findings.

Of note: The above red flags for low back pain are all based on expert opinion,¹¹ and the positive predictive value of a red flag is always low because of the low prevalence of serious spinal pathologies.¹²

Striking a proper balance. This case emphasizes the necessity to keep uncommon causes—such as nontraumatic spinal stroke, which has a prevalence of about 5% to 8% of all acute myelopathies—in the differential diagnosis.³

Continue to: We recommend watchful...

We recommend watchful waiting coupled with communication with the patient regarding monitoring for changes in symptoms over time.¹¹ Any changes in symptoms concerning for underlying spinal cord injury indicate necessity for transfer to a tertiary care center (if possible), along with immediate evaluation with imaging—including computed tomography angiography of the abdomen to rule out aortic dissection (1%-2% of all spinal cord infarcts), followed by a specialist consultation based on the findings.³

Our patient

Our patient was discharged to rehabilitation on hospital Day 5, after progressive return of lower extremity strength. At the 2-month follow-up visit, she demonstrated grade 4+ strength throughout her lower extremities bilaterally. Weakness was predominant at the hip flexors and ankle dorsiflexors, which was consistent with her status at discharge. She had burning pain in the distribution of the L1 dermatome that responded to ibuprofen.

Hypercoagulability work-up was positive for heterozygous FVL mutation without any previous history of venous thromboembolic disease. She was continued on aspirin 325 mg/d, as per American College of Chest Physicians antithrombotic guidelines.¹³

One year later, our patient underwent a follow-up MRI of the thoracic spine, which showed an “owl’s eye” hyperintensity in the anterior cord (FIGURE), a sign that’s often seen in bilateral spinal cord infarction.¹⁴ At 18-month follow-up, the patient had regained her baseline strength with persistent hyperreflexia.

THE TAKEAWAY

Spinal stroke is rare, but a missed diagnosis and lack of treatment can result in long-term morbidity. Therefore, it is prudent to consider this diagnosis in the differential—especially when the patient’s subjective back pain is out of proportion to the clinical examination findings.

CORRESPONDENCE
Srikanth Nithyanandam, MBBS, MS, University of Kentucky Family and Community Medicine, 2195 Harrodsburg Road, Suite 125, Lexington, KY 40504-3504; [email protected].

The vast majority of patients with tendon problems are successfully treated nonoperatively. But which treatments should you try (and when), and which are not quite ready for prime time? This review presents the evidence for the treatment options available to you. But first, it’s important to get our terminology right.

Tendinitis vs tendinosis vs paratenonitis: Words matter

The term “tendinopathy” encompasses many issues related to tendon pathology including tendinitis, tendinosis, and paratenonitis.^1,2 The clinical syndrome consists of pain, swelling, and functional impairment associated with activities of daily living or athletic performance.³ Tendinopathy may be acute or chronic, but most cases result from overuse.¹

In healthy tendons, the collagen fibers are packed tightly and organized in a linear pattern (FIGURE 1A). However, tendons that are chronically overused develop cumulative microtrauma that leads to a degenerative process within the tendon that is slow (typically measured in months) to heal. This is due to the relative lack of vasculature and the slow rate of tissue turnover in tendons.^2,4,5

Sports and manual labor are the most common causes of tendinopathy, but medical conditions including obesity, high blood pressure, diabetes, and high cholesterol are associated risk factors. Medications, particularly fluoroquinolones and statins, can cause tendon problems, and steroids, particularly those injected intratendinously, have been implicated in tendon rupture.^4,6

The term “tendinitis” has long been used for all tendon disorders although it is best reserved for acute inflammatory conditions. For most tendon conditions resulting from overuse, the term “tendinosis” is now more widely recognized and preferred.^7,8 Family physicians (FPs) should recognize that tendinitis and tendinosis differ greatly in pathophysiology and treatment.³

Tendinitis: Not as common as you think

Tendinitis is an acute inflammatory condition that accounts for only about 3% of all tendon disorders.³ Patients presenting with tendinitis usually have acute onset of pain and swelling typically either from a new activity or one to which they are unaccustomed (eg, lateral elbow pain after painting a house) or from an acute injury. Partial tearing of the affected tendon is likely, especially following injury.^2,3

Tendinosis: A degenerative condition

In contrast to the acute inflammation of tendinitis, tendinosis is a degenerative condition induced by chronic overuse. It is typically encountered in athletes and laborers.^2,5,8,9 Tendinotic tissue is generally regarded as noninflammatory, but recent research supports inflammation playing at least a small role, especially in closely associated tissues such as bursae and the paratenon tissue.¹⁰

Continue to: Histologically, tendinosis shows...

Histologically, tendinosis shows loss of the typical linear collagen fiber organization, increased mucoid ground substance, hypercellularity, and increased growth of nerves and vessels (FIGURE 1B).

Tendinosis is not always symptomatic.^5,11 When pain is present, experts have proposed that it is neurogenically derived rather than from local chemical inflammation. This is supported by evidence of increases in the excitatory neurotransmitter glutamate and its receptor N-methyl-D-aspartate in tendinotic tissue with nerve ingrowth. Tendinotic tissue also contains substance P and calcitonin gene-related peptide, neuropeptides that are associated with pain and nociceptive nerve endings.^2,3,6,10

Patients with tendinosis typically present with an insidious onset of a painful, thickened tendon.¹¹ The most common tendons affected include the Achilles, the patellar, the supraspinatus, and the common extensor tendon of the lateral elbow.² Lower extremity tendinosis is common in athletes, while upper extremity tendinopathies are more often work-related.³

Paratenonitis: Inflammation surrounding the tendon

Occasionally, tendinosis may be associated with paratenonitis, which is inflammation of the paratenon (tissue surrounding some tendons).^2,5,10 Paratendinous tissue contains a higher concentration of sensory nerves than the tendon itself and may generate significant discomfort.^10,11

The clinical presentation of paratenonitis includes a swollen and erythematous tendon.⁵ The classic example—de Quervain disease—involves the first dorsal wrist compartment, in which the abductor pollicis longus and extensor pollicis brevis tendons are encased in a synovial sheath. The term tenosynovitis is commonly used to indicate inflammation of both the paratenon and synovial sheath (TABLE 1^2,3,5,6,9-11).⁵

Continue to: Treatment demands time and patience

Treating tendon conditions is challenging for both the patient and the clinician. Improvement takes time and several different treatment strategies may be required for success. Given the large number of available treatment options and the often weak or limited supporting evidence of their efficacy, designing a treatment plan can be difficult. TABLE 2 summarizes the information detailed below about specific treatment options.

First-line treatments. The vast majority of patients with tendon problems are successfully treated nonoperatively. Reasonable first-line treatments, especially for inflammatory conditions like tendinitis, tenosynovitis, and paratenonitis, include relative rest, activity modification, cryotherapy, and bracing.^12-14

Nonsteroidal anti-inflammatory drugs (NSAIDs) for pain control are somewhat controversial. At best, they provide pain relief in the short term (7-14 days); at worst, some studies suggest potential detrimental effects to the tendon.¹⁴ If considered, NSAIDs should be used for no longer than 2 weeks. They are ideally reserved for pain control in patients with acute injuries when an inflammatory condition is likely. An alternative for pain control in inflammatory cases is a short course of oral steroids, but the adverse effects of these medications may be challenging for some patients.

Other options. If these more conservative treatments fail, or the patient is experiencing significant and debilitating pain, FPs may consider a corticosteroid injection. If this fails, or the condition is clearly past an inflammatory stage, then physical therapy should be considered. More advanced treatments, such as platelet-rich plasma injections and percutaneous needle tenotomies, are typically reserved for chronic, recalcitrant cases of tendinosis. Various other treatment options are detailed below and can be used on a case-by-case basis. Surgical management should be considered only as a last resort.

Reserve use of NSAIDs for pain control in patients with acute injuries when an inflammatory condition is likely.

Realize that certain barriers may exist to some of these treatments. With extracorporeal shockwave therapy, for example, access to a machine can be challenging, as they are typically only found in major metropolitan areas. Polidocanol, used during sclerotherapy, can be difficult to obtain in the United States. Another challenge is cost. Not all of these procedures are covered by insurance, and they can be expensive when paying out of pocket.

Continue to: Rehabilitation...

Studies show that eccentric exercises (EEs) help to decrease vascularity and nerve presence in affected tendons, modulate expression of neuronal substances, and may stimulate formation of load-tolerant fibroblasts.^2,3

Plateletrich plasma injections are typically expensive; whole blood is less expensive because there's no manipulation of the blood product.

For Achilles tendinosis, EE is a well-­established treatment supported by multiple randomized controlled trials (RCTs). Improvements in patient satisfaction and pain range from 60% to 90%; evidence suggests greater success in midsubstance vs insertional Achilles tendinosis.¹⁵ The addition of deep-friction massage (DFM), which we’ll discuss in a moment, to EE appears to improve outcomes even more than EE alone.¹⁶

EE is also a beneficial treatment for patellar tendinosis,^3,14 and it appears to benefit rotator cuff tendinosis,³ but research has shown EE for lateral epicondylosis to be no more effective than stretching alone.¹⁷

Recommend deep-friction massage for tendinosis—not inflammatory conditions.

DFM is for treating tendinosis—not inflammatory conditions. Mechanical stimulation of the tissue being massaged releases cell mediators and growth factors that activate fibroblasts. It is typically performed with plastic or metal tools.¹⁶ DFM appears to be a reliable treatment option for the lateral elbow.¹⁸

Extracorporeal shockwave therapy appears promising; evidence is limited

Research has shown that extracorporeal shockwave therapy (ESWT) promotes the production of TGF-β1 and IGF-1 in rat models,² and it is believed to be able to disintegrate calcium deposits and stimulate tissue repair.¹⁴ Research is generally supportive of its effectiveness in treating tendinosis; however, evidence is limited by great variability in studies in terms of treatment intensity, frequency, duration, timing, number of treatments, and use of a local anesthetic.¹⁴ ESWT appears to be useful in augmenting treatment with EE, particularly with regard to the rotator cuff.¹⁹

Continue to: A review of 10 RCTs...

A review of 10 RCTs demonstrated the effectiveness of ESWT for tennis elbow.² ESWT for greater trochanteric pain syndrome (GTPS, formerly known as trochanteric bursitis) appears to be more effective than corticosteroids and home exercises for outcomes at 4 months and equivalent to home exercises at 15 months.²⁰ In patellar tendinosis, ESWT has been shown to be an effective treatment, especially under ultrasound guidance.¹² Studies involving the use of ESWT for Achilles tendinosis have had mixed results for midsubstance tendinosis, and more positive results for insertional tendinosis.¹⁵ For a video on how the therapy is administered, see https://www.youtube.com/watch?v=Fq5yqiWByX4.

Glyceryl trinitrate patches: Mixed results

Basic science studies have shown that nitric oxide modulates tendon healing by enhancing fibroblast proliferation and collagen synthesis,^2,14 but that it should be used with caution in cardiac patients and in those who take PDE-5 inhibitors. Common adverse effects include rash, headache, and dizziness.

Use glyceryl trinitrate patches with caution in cardiac patients and in those who take PDE-5 inhibitors.

In clinical studies, glyceryl trinitrate (GTN) patches show mixed results. For the upper extremity, GTN appears to be helpful for pain in the short term when combined with physical therapy, but long-term positive outcomes have been absent.²¹ In one Level 1 study for patellar tendinosis comparing GTN patches with EE to a placebo patch with EE, no significant difference was noted at 24 weeks.²² Benefit for Achilles tendinosis also appears to be lacking.^3,23

Corticosteroid injections: Mechanism unknown

The mechanism for the beneficial effects of corticosteroid injections (CSIs) for tendinosis remains controversial. Proposed mechanisms include lysis of peritendinous adhesions, disruption of the nociceptors in the region of the injection, and decreased vascularization.^10,15 Given tendinosis is generally regarded as a noninflammatory condition, and the fact that these medications have demonstrated potential negative effects on tendon healing, exercise caution when considering CSIs.^2,24

Although steroids can effectively reduce pain in the short term, intermediate- and long-term studies generally show no difference or worse outcomes when they are compared to no treatment, placebo, or other treatment modalities. In fact, strong evidence exists for negative effects of steroids on lateral epicondylosis in both the intermediate (6 months) and long (1 year) term.²⁴ Particular care is required when administering a CSI for medial epicondylosis, as the ulnar nerve is immediately posterior to the medial epicondyle.²⁵

Continue to: In contrast...

In contrast, CSIs appear to be a reliable treatment option for de Quervain disease.²⁶ Landmark-guided injections for GTPS can improve pain in the short term (< 1 month), but are inferior to either home exercises or ESWT beyond a few months. Thus, CSIs are a reasonable option for pain control in GTPS, but should not be the sole treatment modality.²⁰

Studies regarding corticosteroid use for Achilles and patellar tendinosis have had mixed results. Patients can hope for mild improvement in pain at best, and the risk for relapse and tendon rupture is ever present.²⁷ This is especially concerning given the significant load-bearing of the patellar and Achilles tendons.^14,15 If you are considering a CSI for these purposes, use imaging guidance to ensure the injection is not placed intratendinously.

Platelet-rich plasma and whole blood: Inducing an anabolic healing response

Platelet-rich plasma (PRP) and whole blood injections both aim to deliver autologous growth factors (eg, VEGF, PDGF, and IGF-1) and bioactive mediators to the site of tendinosis to induce an anabolic healing response. PRP therapy differs from whole blood therapy in that it is withdrawn and then concentrated in a centrifuge before being injected. Patients are typically injected under ultrasound guidance. The great variation in PRP preparation, platelet concentration, use of adjunctive treatments, leukocyte concentration, and number and technique of injections makes it difficult to determine the optimal PRP treatment protocol.^10,28,29

In 1 prospective RCT comparing subacromial PRP injections to CSI for the shoulder, the PRP group had better outcomes at 3 months, but similar outcomes at 6 months. The suggestion was made that PRP therapy could be an alternative treatment for individuals with a contraindication to CSIs.³⁰

PRP therapy appears to be an effective treatment option for patellar tendinopathy.^28,31 A Level 1 study comparing dry needle tenotomy and EE to dry needle tenotomy with both PRP therapy and EE found faster recovery in the PRP group.³² In another patellar tendon study comparing ESWT to PRP therapy, both were found to be effective, but PRP performed better in terms of pain, function, and satisfaction at 6 and 12 months.¹² For Achilles tendons, however, the evidence is mixed; case series have had generally positive outcomes, but the only double-blind RCT found no benefit.^28,31

Continue to: In lateral epicondylosis...

In lateral epicondylosis, the use of auto-logous whole blood or PRP injections appears to help both pain and function, with several studies failing to demonstrate superiority of 1 modality over the other.^24,25,28,33 This raises the issue of whether PRP therapy is any more effective than whole blood for the treatment of other tendinopathies. Unfortunately, there is a paucity of studies comparing the effectiveness of 1 modality to the other, apart from those for lateral epicondylosis.

Prolotherapy: An option for these 3 conditions

Prolotherapy involves the injection of hypertonic dextrose and local anesthetic, which is believed to lead to an upregulation of inflammatory mediators and growth factors. This treatment usually involves several injections spaced 2 to 6 weeks apart over several months. High-quality studies are not available to clarify the optimal dextrose concentration or number of injections required. The few high-quality studies available support prolotherapy for lateral epicondylosis, rotator cuff tendinopathy, and Osgood Schlatter disease. Lesser-quality studies support its use for refractory pain of the Achilles, hip adductors, and plantar fascia.^24,34

Sclerotherapy: Not just for veins

As discussed earlier, tendinotic tissue can have neovascularization that is easily detected on Doppler ultrasound. Sensory nerves typically grow alongside the new vessels. Sclerosing agents, such as polidocanol, can be injected with ultrasound guidance into areas of neovascularization, with the intention of causing denervation and pain relief.¹⁵ Neovascularization does not always correlate with pathology, so careful patient selection is necessary.³⁵

Exercise caution when considering corticosteroid injections for tendinosis.

Studies of sclerotherapy for patellar tendinopathy are generally favorable. One comparing sclerotherapy to arthroscopic debridement showed improvement in pain from both treatments at 6 and 12 months, but the arthroscopy group had less pain, better satisfaction scores, and a faster return to sport.¹⁴ Sclerotherapy is also effective for Achilles tendinosis.¹⁵

Stem cells: Not at this time

Stem cell use for tendinosis is based on the theory that these cells possess the capability to differentiate into tenocytes to produce new, healthy tendon tissue. Additionally, stem cell injections are believed to create a local immune response, recruiting local growth factors and cytokines to aide in tendon repair. A recent systematic review failed to identify any high-quality studies (Level 4 data at best) supporting the use of stem cells in tendinopathy, and the researchers did not recommend stem cell use outside of clinical trials at this time.³⁶

Continue to: Percutaneous needle tenotomy...

Percutaneous needle tenotomy is thought to benefit tendinosis by disrupting the tendinotic tissue via needling, while simultaneously causing bleeding and the release of growth factors to aid in healing. Unlike surgical ­tenotomy, the procedure is typically performed with ultrasound guidance in the office or other ambulatory setting. After local anesthesia is administered, a needle is passed multiple times through the entire region of abnormality noted on ultrasound. Generally, around 20 to 30 needle fenestrations are performed.^37,38

Consider prolotherapy for lateral epicondylosis, rotator cuff tendinopathy, and Osgood Schlatter disease.

In one retrospective study evaluating 47 patellar tendons, 81% had excellent or good results.³⁸ In a retrospective study for lateral epicondylosis, 80% had good to excellent results.³⁹

CORRESPONDENCE
Kyle Goerl, MD, CAQSM, Lafene Health Center, 1105 Sunset Avenue, Manhattan, KS, 66502-3761; [email protected].

The vast majority of patients with tendon problems are successfully treated nonoperatively. But which treatments should you try (and when), and which are not quite ready for prime time? This review presents the evidence for the treatment options available to you. But first, it’s important to get our terminology right.

Tendinitis vs tendinosis vs paratenonitis: Words matter

The term “tendinopathy” encompasses many issues related to tendon pathology including tendinitis, tendinosis, and paratenonitis.^1,2 The clinical syndrome consists of pain, swelling, and functional impairment associated with activities of daily living or athletic performance.³ Tendinopathy may be acute or chronic, but most cases result from overuse.¹

In healthy tendons, the collagen fibers are packed tightly and organized in a linear pattern (FIGURE 1A). However, tendons that are chronically overused develop cumulative microtrauma that leads to a degenerative process within the tendon that is slow (typically measured in months) to heal. This is due to the relative lack of vasculature and the slow rate of tissue turnover in tendons.^2,4,5

Sports and manual labor are the most common causes of tendinopathy, but medical conditions including obesity, high blood pressure, diabetes, and high cholesterol are associated risk factors. Medications, particularly fluoroquinolones and statins, can cause tendon problems, and steroids, particularly those injected intratendinously, have been implicated in tendon rupture.^4,6

The term “tendinitis” has long been used for all tendon disorders although it is best reserved for acute inflammatory conditions. For most tendon conditions resulting from overuse, the term “tendinosis” is now more widely recognized and preferred.^7,8 Family physicians (FPs) should recognize that tendinitis and tendinosis differ greatly in pathophysiology and treatment.³

Tendinitis: Not as common as you think

Tendinitis is an acute inflammatory condition that accounts for only about 3% of all tendon disorders.³ Patients presenting with tendinitis usually have acute onset of pain and swelling typically either from a new activity or one to which they are unaccustomed (eg, lateral elbow pain after painting a house) or from an acute injury. Partial tearing of the affected tendon is likely, especially following injury.^2,3

Tendinosis: A degenerative condition

In contrast to the acute inflammation of tendinitis, tendinosis is a degenerative condition induced by chronic overuse. It is typically encountered in athletes and laborers.^2,5,8,9 Tendinotic tissue is generally regarded as noninflammatory, but recent research supports inflammation playing at least a small role, especially in closely associated tissues such as bursae and the paratenon tissue.¹⁰

Continue to: Histologically, tendinosis shows...

Histologically, tendinosis shows loss of the typical linear collagen fiber organization, increased mucoid ground substance, hypercellularity, and increased growth of nerves and vessels (FIGURE 1B).

Tendinosis is not always symptomatic.^5,11 When pain is present, experts have proposed that it is neurogenically derived rather than from local chemical inflammation. This is supported by evidence of increases in the excitatory neurotransmitter glutamate and its receptor N-methyl-D-aspartate in tendinotic tissue with nerve ingrowth. Tendinotic tissue also contains substance P and calcitonin gene-related peptide, neuropeptides that are associated with pain and nociceptive nerve endings.^2,3,6,10

Patients with tendinosis typically present with an insidious onset of a painful, thickened tendon.¹¹ The most common tendons affected include the Achilles, the patellar, the supraspinatus, and the common extensor tendon of the lateral elbow.² Lower extremity tendinosis is common in athletes, while upper extremity tendinopathies are more often work-related.³

Paratenonitis: Inflammation surrounding the tendon

Occasionally, tendinosis may be associated with paratenonitis, which is inflammation of the paratenon (tissue surrounding some tendons).^2,5,10 Paratendinous tissue contains a higher concentration of sensory nerves than the tendon itself and may generate significant discomfort.^10,11

The clinical presentation of paratenonitis includes a swollen and erythematous tendon.⁵ The classic example—de Quervain disease—involves the first dorsal wrist compartment, in which the abductor pollicis longus and extensor pollicis brevis tendons are encased in a synovial sheath. The term tenosynovitis is commonly used to indicate inflammation of both the paratenon and synovial sheath (TABLE 1^2,3,5,6,9-11).⁵

Continue to: Treatment demands time and patience

Treating tendon conditions is challenging for both the patient and the clinician. Improvement takes time and several different treatment strategies may be required for success. Given the large number of available treatment options and the often weak or limited supporting evidence of their efficacy, designing a treatment plan can be difficult. TABLE 2 summarizes the information detailed below about specific treatment options.

First-line treatments. The vast majority of patients with tendon problems are successfully treated nonoperatively. Reasonable first-line treatments, especially for inflammatory conditions like tendinitis, tenosynovitis, and paratenonitis, include relative rest, activity modification, cryotherapy, and bracing.^12-14

Nonsteroidal anti-inflammatory drugs (NSAIDs) for pain control are somewhat controversial. At best, they provide pain relief in the short term (7-14 days); at worst, some studies suggest potential detrimental effects to the tendon.¹⁴ If considered, NSAIDs should be used for no longer than 2 weeks. They are ideally reserved for pain control in patients with acute injuries when an inflammatory condition is likely. An alternative for pain control in inflammatory cases is a short course of oral steroids, but the adverse effects of these medications may be challenging for some patients.

Other options. If these more conservative treatments fail, or the patient is experiencing significant and debilitating pain, FPs may consider a corticosteroid injection. If this fails, or the condition is clearly past an inflammatory stage, then physical therapy should be considered. More advanced treatments, such as platelet-rich plasma injections and percutaneous needle tenotomies, are typically reserved for chronic, recalcitrant cases of tendinosis. Various other treatment options are detailed below and can be used on a case-by-case basis. Surgical management should be considered only as a last resort.

Reserve use of NSAIDs for pain control in patients with acute injuries when an inflammatory condition is likely.

Realize that certain barriers may exist to some of these treatments. With extracorporeal shockwave therapy, for example, access to a machine can be challenging, as they are typically only found in major metropolitan areas. Polidocanol, used during sclerotherapy, can be difficult to obtain in the United States. Another challenge is cost. Not all of these procedures are covered by insurance, and they can be expensive when paying out of pocket.

Continue to: Rehabilitation...

Studies show that eccentric exercises (EEs) help to decrease vascularity and nerve presence in affected tendons, modulate expression of neuronal substances, and may stimulate formation of load-tolerant fibroblasts.^2,3

Plateletrich plasma injections are typically expensive; whole blood is less expensive because there's no manipulation of the blood product.

For Achilles tendinosis, EE is a well-­established treatment supported by multiple randomized controlled trials (RCTs). Improvements in patient satisfaction and pain range from 60% to 90%; evidence suggests greater success in midsubstance vs insertional Achilles tendinosis.¹⁵ The addition of deep-friction massage (DFM), which we’ll discuss in a moment, to EE appears to improve outcomes even more than EE alone.¹⁶

EE is also a beneficial treatment for patellar tendinosis,^3,14 and it appears to benefit rotator cuff tendinosis,³ but research has shown EE for lateral epicondylosis to be no more effective than stretching alone.¹⁷

Recommend deep-friction massage for tendinosis—not inflammatory conditions.

DFM is for treating tendinosis—not inflammatory conditions. Mechanical stimulation of the tissue being massaged releases cell mediators and growth factors that activate fibroblasts. It is typically performed with plastic or metal tools.¹⁶ DFM appears to be a reliable treatment option for the lateral elbow.¹⁸

Extracorporeal shockwave therapy appears promising; evidence is limited

Research has shown that extracorporeal shockwave therapy (ESWT) promotes the production of TGF-β1 and IGF-1 in rat models,² and it is believed to be able to disintegrate calcium deposits and stimulate tissue repair.¹⁴ Research is generally supportive of its effectiveness in treating tendinosis; however, evidence is limited by great variability in studies in terms of treatment intensity, frequency, duration, timing, number of treatments, and use of a local anesthetic.¹⁴ ESWT appears to be useful in augmenting treatment with EE, particularly with regard to the rotator cuff.¹⁹

Continue to: A review of 10 RCTs...

A review of 10 RCTs demonstrated the effectiveness of ESWT for tennis elbow.² ESWT for greater trochanteric pain syndrome (GTPS, formerly known as trochanteric bursitis) appears to be more effective than corticosteroids and home exercises for outcomes at 4 months and equivalent to home exercises at 15 months.²⁰ In patellar tendinosis, ESWT has been shown to be an effective treatment, especially under ultrasound guidance.¹² Studies involving the use of ESWT for Achilles tendinosis have had mixed results for midsubstance tendinosis, and more positive results for insertional tendinosis.¹⁵ For a video on how the therapy is administered, see https://www.youtube.com/watch?v=Fq5yqiWByX4.

Glyceryl trinitrate patches: Mixed results

Basic science studies have shown that nitric oxide modulates tendon healing by enhancing fibroblast proliferation and collagen synthesis,^2,14 but that it should be used with caution in cardiac patients and in those who take PDE-5 inhibitors. Common adverse effects include rash, headache, and dizziness.

Use glyceryl trinitrate patches with caution in cardiac patients and in those who take PDE-5 inhibitors.

In clinical studies, glyceryl trinitrate (GTN) patches show mixed results. For the upper extremity, GTN appears to be helpful for pain in the short term when combined with physical therapy, but long-term positive outcomes have been absent.²¹ In one Level 1 study for patellar tendinosis comparing GTN patches with EE to a placebo patch with EE, no significant difference was noted at 24 weeks.²² Benefit for Achilles tendinosis also appears to be lacking.^3,23

Corticosteroid injections: Mechanism unknown

The mechanism for the beneficial effects of corticosteroid injections (CSIs) for tendinosis remains controversial. Proposed mechanisms include lysis of peritendinous adhesions, disruption of the nociceptors in the region of the injection, and decreased vascularization.^10,15 Given tendinosis is generally regarded as a noninflammatory condition, and the fact that these medications have demonstrated potential negative effects on tendon healing, exercise caution when considering CSIs.^2,24

Although steroids can effectively reduce pain in the short term, intermediate- and long-term studies generally show no difference or worse outcomes when they are compared to no treatment, placebo, or other treatment modalities. In fact, strong evidence exists for negative effects of steroids on lateral epicondylosis in both the intermediate (6 months) and long (1 year) term.²⁴ Particular care is required when administering a CSI for medial epicondylosis, as the ulnar nerve is immediately posterior to the medial epicondyle.²⁵

Continue to: In contrast...

In contrast, CSIs appear to be a reliable treatment option for de Quervain disease.²⁶ Landmark-guided injections for GTPS can improve pain in the short term (< 1 month), but are inferior to either home exercises or ESWT beyond a few months. Thus, CSIs are a reasonable option for pain control in GTPS, but should not be the sole treatment modality.²⁰

Studies regarding corticosteroid use for Achilles and patellar tendinosis have had mixed results. Patients can hope for mild improvement in pain at best, and the risk for relapse and tendon rupture is ever present.²⁷ This is especially concerning given the significant load-bearing of the patellar and Achilles tendons.^14,15 If you are considering a CSI for these purposes, use imaging guidance to ensure the injection is not placed intratendinously.

Platelet-rich plasma and whole blood: Inducing an anabolic healing response

Platelet-rich plasma (PRP) and whole blood injections both aim to deliver autologous growth factors (eg, VEGF, PDGF, and IGF-1) and bioactive mediators to the site of tendinosis to induce an anabolic healing response. PRP therapy differs from whole blood therapy in that it is withdrawn and then concentrated in a centrifuge before being injected. Patients are typically injected under ultrasound guidance. The great variation in PRP preparation, platelet concentration, use of adjunctive treatments, leukocyte concentration, and number and technique of injections makes it difficult to determine the optimal PRP treatment protocol.^10,28,29

In 1 prospective RCT comparing subacromial PRP injections to CSI for the shoulder, the PRP group had better outcomes at 3 months, but similar outcomes at 6 months. The suggestion was made that PRP therapy could be an alternative treatment for individuals with a contraindication to CSIs.³⁰

PRP therapy appears to be an effective treatment option for patellar tendinopathy.^28,31 A Level 1 study comparing dry needle tenotomy and EE to dry needle tenotomy with both PRP therapy and EE found faster recovery in the PRP group.³² In another patellar tendon study comparing ESWT to PRP therapy, both were found to be effective, but PRP performed better in terms of pain, function, and satisfaction at 6 and 12 months.¹² For Achilles tendons, however, the evidence is mixed; case series have had generally positive outcomes, but the only double-blind RCT found no benefit.^28,31

Continue to: In lateral epicondylosis...

In lateral epicondylosis, the use of auto-logous whole blood or PRP injections appears to help both pain and function, with several studies failing to demonstrate superiority of 1 modality over the other.^24,25,28,33 This raises the issue of whether PRP therapy is any more effective than whole blood for the treatment of other tendinopathies. Unfortunately, there is a paucity of studies comparing the effectiveness of 1 modality to the other, apart from those for lateral epicondylosis.

Prolotherapy: An option for these 3 conditions

Prolotherapy involves the injection of hypertonic dextrose and local anesthetic, which is believed to lead to an upregulation of inflammatory mediators and growth factors. This treatment usually involves several injections spaced 2 to 6 weeks apart over several months. High-quality studies are not available to clarify the optimal dextrose concentration or number of injections required. The few high-quality studies available support prolotherapy for lateral epicondylosis, rotator cuff tendinopathy, and Osgood Schlatter disease. Lesser-quality studies support its use for refractory pain of the Achilles, hip adductors, and plantar fascia.^24,34

Sclerotherapy: Not just for veins

As discussed earlier, tendinotic tissue can have neovascularization that is easily detected on Doppler ultrasound. Sensory nerves typically grow alongside the new vessels. Sclerosing agents, such as polidocanol, can be injected with ultrasound guidance into areas of neovascularization, with the intention of causing denervation and pain relief.¹⁵ Neovascularization does not always correlate with pathology, so careful patient selection is necessary.³⁵

Exercise caution when considering corticosteroid injections for tendinosis.

Studies of sclerotherapy for patellar tendinopathy are generally favorable. One comparing sclerotherapy to arthroscopic debridement showed improvement in pain from both treatments at 6 and 12 months, but the arthroscopy group had less pain, better satisfaction scores, and a faster return to sport.¹⁴ Sclerotherapy is also effective for Achilles tendinosis.¹⁵

Stem cells: Not at this time

Stem cell use for tendinosis is based on the theory that these cells possess the capability to differentiate into tenocytes to produce new, healthy tendon tissue. Additionally, stem cell injections are believed to create a local immune response, recruiting local growth factors and cytokines to aide in tendon repair. A recent systematic review failed to identify any high-quality studies (Level 4 data at best) supporting the use of stem cells in tendinopathy, and the researchers did not recommend stem cell use outside of clinical trials at this time.³⁶

Continue to: Percutaneous needle tenotomy...

Percutaneous needle tenotomy is thought to benefit tendinosis by disrupting the tendinotic tissue via needling, while simultaneously causing bleeding and the release of growth factors to aid in healing. Unlike surgical ­tenotomy, the procedure is typically performed with ultrasound guidance in the office or other ambulatory setting. After local anesthesia is administered, a needle is passed multiple times through the entire region of abnormality noted on ultrasound. Generally, around 20 to 30 needle fenestrations are performed.^37,38

Consider prolotherapy for lateral epicondylosis, rotator cuff tendinopathy, and Osgood Schlatter disease.

In one retrospective study evaluating 47 patellar tendons, 81% had excellent or good results.³⁸ In a retrospective study for lateral epicondylosis, 80% had good to excellent results.³⁹

CORRESPONDENCE
Kyle Goerl, MD, CAQSM, Lafene Health Center, 1105 Sunset Avenue, Manhattan, KS, 66502-3761; [email protected].

The vast majority of patients with tendon problems are successfully treated nonoperatively. But which treatments should you try (and when), and which are not quite ready for prime time? This review presents the evidence for the treatment options available to you. But first, it’s important to get our terminology right.

Tendinitis vs tendinosis vs paratenonitis: Words matter

The term “tendinopathy” encompasses many issues related to tendon pathology including tendinitis, tendinosis, and paratenonitis.^1,2 The clinical syndrome consists of pain, swelling, and functional impairment associated with activities of daily living or athletic performance.³ Tendinopathy may be acute or chronic, but most cases result from overuse.¹

In healthy tendons, the collagen fibers are packed tightly and organized in a linear pattern (FIGURE 1A). However, tendons that are chronically overused develop cumulative microtrauma that leads to a degenerative process within the tendon that is slow (typically measured in months) to heal. This is due to the relative lack of vasculature and the slow rate of tissue turnover in tendons.^2,4,5

Sports and manual labor are the most common causes of tendinopathy, but medical conditions including obesity, high blood pressure, diabetes, and high cholesterol are associated risk factors. Medications, particularly fluoroquinolones and statins, can cause tendon problems, and steroids, particularly those injected intratendinously, have been implicated in tendon rupture.^4,6

The term “tendinitis” has long been used for all tendon disorders although it is best reserved for acute inflammatory conditions. For most tendon conditions resulting from overuse, the term “tendinosis” is now more widely recognized and preferred.^7,8 Family physicians (FPs) should recognize that tendinitis and tendinosis differ greatly in pathophysiology and treatment.³

Tendinitis: Not as common as you think

Tendinitis is an acute inflammatory condition that accounts for only about 3% of all tendon disorders.³ Patients presenting with tendinitis usually have acute onset of pain and swelling typically either from a new activity or one to which they are unaccustomed (eg, lateral elbow pain after painting a house) or from an acute injury. Partial tearing of the affected tendon is likely, especially following injury.^2,3

Tendinosis: A degenerative condition

In contrast to the acute inflammation of tendinitis, tendinosis is a degenerative condition induced by chronic overuse. It is typically encountered in athletes and laborers.^2,5,8,9 Tendinotic tissue is generally regarded as noninflammatory, but recent research supports inflammation playing at least a small role, especially in closely associated tissues such as bursae and the paratenon tissue.¹⁰

Continue to: Histologically, tendinosis shows...

Histologically, tendinosis shows loss of the typical linear collagen fiber organization, increased mucoid ground substance, hypercellularity, and increased growth of nerves and vessels (FIGURE 1B).

Tendinosis is not always symptomatic.^5,11 When pain is present, experts have proposed that it is neurogenically derived rather than from local chemical inflammation. This is supported by evidence of increases in the excitatory neurotransmitter glutamate and its receptor N-methyl-D-aspartate in tendinotic tissue with nerve ingrowth. Tendinotic tissue also contains substance P and calcitonin gene-related peptide, neuropeptides that are associated with pain and nociceptive nerve endings.^2,3,6,10

Patients with tendinosis typically present with an insidious onset of a painful, thickened tendon.¹¹ The most common tendons affected include the Achilles, the patellar, the supraspinatus, and the common extensor tendon of the lateral elbow.² Lower extremity tendinosis is common in athletes, while upper extremity tendinopathies are more often work-related.³

Paratenonitis: Inflammation surrounding the tendon

Occasionally, tendinosis may be associated with paratenonitis, which is inflammation of the paratenon (tissue surrounding some tendons).^2,5,10 Paratendinous tissue contains a higher concentration of sensory nerves than the tendon itself and may generate significant discomfort.^10,11

The clinical presentation of paratenonitis includes a swollen and erythematous tendon.⁵ The classic example—de Quervain disease—involves the first dorsal wrist compartment, in which the abductor pollicis longus and extensor pollicis brevis tendons are encased in a synovial sheath. The term tenosynovitis is commonly used to indicate inflammation of both the paratenon and synovial sheath (TABLE 1^2,3,5,6,9-11).⁵

Continue to: Treatment demands time and patience

Treating tendon conditions is challenging for both the patient and the clinician. Improvement takes time and several different treatment strategies may be required for success. Given the large number of available treatment options and the often weak or limited supporting evidence of their efficacy, designing a treatment plan can be difficult. TABLE 2 summarizes the information detailed below about specific treatment options.

First-line treatments. The vast majority of patients with tendon problems are successfully treated nonoperatively. Reasonable first-line treatments, especially for inflammatory conditions like tendinitis, tenosynovitis, and paratenonitis, include relative rest, activity modification, cryotherapy, and bracing.^12-14

Nonsteroidal anti-inflammatory drugs (NSAIDs) for pain control are somewhat controversial. At best, they provide pain relief in the short term (7-14 days); at worst, some studies suggest potential detrimental effects to the tendon.¹⁴ If considered, NSAIDs should be used for no longer than 2 weeks. They are ideally reserved for pain control in patients with acute injuries when an inflammatory condition is likely. An alternative for pain control in inflammatory cases is a short course of oral steroids, but the adverse effects of these medications may be challenging for some patients.

Other options. If these more conservative treatments fail, or the patient is experiencing significant and debilitating pain, FPs may consider a corticosteroid injection. If this fails, or the condition is clearly past an inflammatory stage, then physical therapy should be considered. More advanced treatments, such as platelet-rich plasma injections and percutaneous needle tenotomies, are typically reserved for chronic, recalcitrant cases of tendinosis. Various other treatment options are detailed below and can be used on a case-by-case basis. Surgical management should be considered only as a last resort.

Reserve use of NSAIDs for pain control in patients with acute injuries when an inflammatory condition is likely.

Realize that certain barriers may exist to some of these treatments. With extracorporeal shockwave therapy, for example, access to a machine can be challenging, as they are typically only found in major metropolitan areas. Polidocanol, used during sclerotherapy, can be difficult to obtain in the United States. Another challenge is cost. Not all of these procedures are covered by insurance, and they can be expensive when paying out of pocket.

Continue to: Rehabilitation...

Studies show that eccentric exercises (EEs) help to decrease vascularity and nerve presence in affected tendons, modulate expression of neuronal substances, and may stimulate formation of load-tolerant fibroblasts.^2,3

Plateletrich plasma injections are typically expensive; whole blood is less expensive because there's no manipulation of the blood product.

For Achilles tendinosis, EE is a well-­established treatment supported by multiple randomized controlled trials (RCTs). Improvements in patient satisfaction and pain range from 60% to 90%; evidence suggests greater success in midsubstance vs insertional Achilles tendinosis.¹⁵ The addition of deep-friction massage (DFM), which we’ll discuss in a moment, to EE appears to improve outcomes even more than EE alone.¹⁶

EE is also a beneficial treatment for patellar tendinosis,^3,14 and it appears to benefit rotator cuff tendinosis,³ but research has shown EE for lateral epicondylosis to be no more effective than stretching alone.¹⁷

Recommend deep-friction massage for tendinosis—not inflammatory conditions.

DFM is for treating tendinosis—not inflammatory conditions. Mechanical stimulation of the tissue being massaged releases cell mediators and growth factors that activate fibroblasts. It is typically performed with plastic or metal tools.¹⁶ DFM appears to be a reliable treatment option for the lateral elbow.¹⁸

Extracorporeal shockwave therapy appears promising; evidence is limited

Research has shown that extracorporeal shockwave therapy (ESWT) promotes the production of TGF-β1 and IGF-1 in rat models,² and it is believed to be able to disintegrate calcium deposits and stimulate tissue repair.¹⁴ Research is generally supportive of its effectiveness in treating tendinosis; however, evidence is limited by great variability in studies in terms of treatment intensity, frequency, duration, timing, number of treatments, and use of a local anesthetic.¹⁴ ESWT appears to be useful in augmenting treatment with EE, particularly with regard to the rotator cuff.¹⁹

Continue to: A review of 10 RCTs...

A review of 10 RCTs demonstrated the effectiveness of ESWT for tennis elbow.² ESWT for greater trochanteric pain syndrome (GTPS, formerly known as trochanteric bursitis) appears to be more effective than corticosteroids and home exercises for outcomes at 4 months and equivalent to home exercises at 15 months.²⁰ In patellar tendinosis, ESWT has been shown to be an effective treatment, especially under ultrasound guidance.¹² Studies involving the use of ESWT for Achilles tendinosis have had mixed results for midsubstance tendinosis, and more positive results for insertional tendinosis.¹⁵ For a video on how the therapy is administered, see https://www.youtube.com/watch?v=Fq5yqiWByX4.

Glyceryl trinitrate patches: Mixed results

Basic science studies have shown that nitric oxide modulates tendon healing by enhancing fibroblast proliferation and collagen synthesis,^2,14 but that it should be used with caution in cardiac patients and in those who take PDE-5 inhibitors. Common adverse effects include rash, headache, and dizziness.

Use glyceryl trinitrate patches with caution in cardiac patients and in those who take PDE-5 inhibitors.

In clinical studies, glyceryl trinitrate (GTN) patches show mixed results. For the upper extremity, GTN appears to be helpful for pain in the short term when combined with physical therapy, but long-term positive outcomes have been absent.²¹ In one Level 1 study for patellar tendinosis comparing GTN patches with EE to a placebo patch with EE, no significant difference was noted at 24 weeks.²² Benefit for Achilles tendinosis also appears to be lacking.^3,23

Corticosteroid injections: Mechanism unknown

The mechanism for the beneficial effects of corticosteroid injections (CSIs) for tendinosis remains controversial. Proposed mechanisms include lysis of peritendinous adhesions, disruption of the nociceptors in the region of the injection, and decreased vascularization.^10,15 Given tendinosis is generally regarded as a noninflammatory condition, and the fact that these medications have demonstrated potential negative effects on tendon healing, exercise caution when considering CSIs.^2,24

Although steroids can effectively reduce pain in the short term, intermediate- and long-term studies generally show no difference or worse outcomes when they are compared to no treatment, placebo, or other treatment modalities. In fact, strong evidence exists for negative effects of steroids on lateral epicondylosis in both the intermediate (6 months) and long (1 year) term.²⁴ Particular care is required when administering a CSI for medial epicondylosis, as the ulnar nerve is immediately posterior to the medial epicondyle.²⁵

Continue to: In contrast...

In contrast, CSIs appear to be a reliable treatment option for de Quervain disease.²⁶ Landmark-guided injections for GTPS can improve pain in the short term (< 1 month), but are inferior to either home exercises or ESWT beyond a few months. Thus, CSIs are a reasonable option for pain control in GTPS, but should not be the sole treatment modality.²⁰

Studies regarding corticosteroid use for Achilles and patellar tendinosis have had mixed results. Patients can hope for mild improvement in pain at best, and the risk for relapse and tendon rupture is ever present.²⁷ This is especially concerning given the significant load-bearing of the patellar and Achilles tendons.^14,15 If you are considering a CSI for these purposes, use imaging guidance to ensure the injection is not placed intratendinously.

Platelet-rich plasma and whole blood: Inducing an anabolic healing response

Platelet-rich plasma (PRP) and whole blood injections both aim to deliver autologous growth factors (eg, VEGF, PDGF, and IGF-1) and bioactive mediators to the site of tendinosis to induce an anabolic healing response. PRP therapy differs from whole blood therapy in that it is withdrawn and then concentrated in a centrifuge before being injected. Patients are typically injected under ultrasound guidance. The great variation in PRP preparation, platelet concentration, use of adjunctive treatments, leukocyte concentration, and number and technique of injections makes it difficult to determine the optimal PRP treatment protocol.^10,28,29

In 1 prospective RCT comparing subacromial PRP injections to CSI for the shoulder, the PRP group had better outcomes at 3 months, but similar outcomes at 6 months. The suggestion was made that PRP therapy could be an alternative treatment for individuals with a contraindication to CSIs.³⁰

PRP therapy appears to be an effective treatment option for patellar tendinopathy.^28,31 A Level 1 study comparing dry needle tenotomy and EE to dry needle tenotomy with both PRP therapy and EE found faster recovery in the PRP group.³² In another patellar tendon study comparing ESWT to PRP therapy, both were found to be effective, but PRP performed better in terms of pain, function, and satisfaction at 6 and 12 months.¹² For Achilles tendons, however, the evidence is mixed; case series have had generally positive outcomes, but the only double-blind RCT found no benefit.^28,31

Continue to: In lateral epicondylosis...

In lateral epicondylosis, the use of auto-logous whole blood or PRP injections appears to help both pain and function, with several studies failing to demonstrate superiority of 1 modality over the other.^24,25,28,33 This raises the issue of whether PRP therapy is any more effective than whole blood for the treatment of other tendinopathies. Unfortunately, there is a paucity of studies comparing the effectiveness of 1 modality to the other, apart from those for lateral epicondylosis.

Prolotherapy: An option for these 3 conditions

Prolotherapy involves the injection of hypertonic dextrose and local anesthetic, which is believed to lead to an upregulation of inflammatory mediators and growth factors. This treatment usually involves several injections spaced 2 to 6 weeks apart over several months. High-quality studies are not available to clarify the optimal dextrose concentration or number of injections required. The few high-quality studies available support prolotherapy for lateral epicondylosis, rotator cuff tendinopathy, and Osgood Schlatter disease. Lesser-quality studies support its use for refractory pain of the Achilles, hip adductors, and plantar fascia.^24,34

Sclerotherapy: Not just for veins

As discussed earlier, tendinotic tissue can have neovascularization that is easily detected on Doppler ultrasound. Sensory nerves typically grow alongside the new vessels. Sclerosing agents, such as polidocanol, can be injected with ultrasound guidance into areas of neovascularization, with the intention of causing denervation and pain relief.¹⁵ Neovascularization does not always correlate with pathology, so careful patient selection is necessary.³⁵

Exercise caution when considering corticosteroid injections for tendinosis.

Studies of sclerotherapy for patellar tendinopathy are generally favorable. One comparing sclerotherapy to arthroscopic debridement showed improvement in pain from both treatments at 6 and 12 months, but the arthroscopy group had less pain, better satisfaction scores, and a faster return to sport.¹⁴ Sclerotherapy is also effective for Achilles tendinosis.¹⁵

Stem cells: Not at this time

Stem cell use for tendinosis is based on the theory that these cells possess the capability to differentiate into tenocytes to produce new, healthy tendon tissue. Additionally, stem cell injections are believed to create a local immune response, recruiting local growth factors and cytokines to aide in tendon repair. A recent systematic review failed to identify any high-quality studies (Level 4 data at best) supporting the use of stem cells in tendinopathy, and the researchers did not recommend stem cell use outside of clinical trials at this time.³⁶

Continue to: Percutaneous needle tenotomy...

Percutaneous needle tenotomy is thought to benefit tendinosis by disrupting the tendinotic tissue via needling, while simultaneously causing bleeding and the release of growth factors to aid in healing. Unlike surgical ­tenotomy, the procedure is typically performed with ultrasound guidance in the office or other ambulatory setting. After local anesthesia is administered, a needle is passed multiple times through the entire region of abnormality noted on ultrasound. Generally, around 20 to 30 needle fenestrations are performed.^37,38

Consider prolotherapy for lateral epicondylosis, rotator cuff tendinopathy, and Osgood Schlatter disease.

In one retrospective study evaluating 47 patellar tendons, 81% had excellent or good results.³⁸ In a retrospective study for lateral epicondylosis, 80% had good to excellent results.³⁹

CORRESPONDENCE
Kyle Goerl, MD, CAQSM, Lafene Health Center, 1105 Sunset Avenue, Manhattan, KS, 66502-3761; [email protected].

Annual opioid prescriptions for American aged 65 years and older are more than double the amount received by adults under age 65, according to the Agency for Healthcare Quality and Research.

Elderly adults with chronic and acute pain obtained an average of 774 morphine milligram equivalents (MMEs) of prescription opioids annually during 2015-2016 from outpatient clinicians, compared with 376 MMEs a year for nonelderly adults, said Asako S. Moriya, PhD, and G. Edward Miller, PhD, of the AHRQ.

Narrowing the age groups shows that opioid MMEs increased with age, starting at 49 MMEs for 18- to 26-year-olds and rising to a high of 856 MMEs in the 65- to 74-year-old group, before dropping off in the oldest adults, the investigators said in a Medical Expenditure Panel Survey (MEPS) research findings report.

The analysis included “all opioid medications that are commonly used to treat pain” and excluded respiratory agents, antitussives, and drugs used for medication-assisted treatment, they noted. The MEPS data cover prescriptions purchased or obtained in outpatient settings but not those administered in inpatient settings or in clinics or physician offices.

[email protected]

Annual opioid prescriptions for American aged 65 years and older are more than double the amount received by adults under age 65, according to the Agency for Healthcare Quality and Research.

Elderly adults with chronic and acute pain obtained an average of 774 morphine milligram equivalents (MMEs) of prescription opioids annually during 2015-2016 from outpatient clinicians, compared with 376 MMEs a year for nonelderly adults, said Asako S. Moriya, PhD, and G. Edward Miller, PhD, of the AHRQ.

Narrowing the age groups shows that opioid MMEs increased with age, starting at 49 MMEs for 18- to 26-year-olds and rising to a high of 856 MMEs in the 65- to 74-year-old group, before dropping off in the oldest adults, the investigators said in a Medical Expenditure Panel Survey (MEPS) research findings report.

The analysis included “all opioid medications that are commonly used to treat pain” and excluded respiratory agents, antitussives, and drugs used for medication-assisted treatment, they noted. The MEPS data cover prescriptions purchased or obtained in outpatient settings but not those administered in inpatient settings or in clinics or physician offices.

[email protected]

Annual opioid prescriptions for American aged 65 years and older are more than double the amount received by adults under age 65, according to the Agency for Healthcare Quality and Research.

Elderly adults with chronic and acute pain obtained an average of 774 morphine milligram equivalents (MMEs) of prescription opioids annually during 2015-2016 from outpatient clinicians, compared with 376 MMEs a year for nonelderly adults, said Asako S. Moriya, PhD, and G. Edward Miller, PhD, of the AHRQ.

Narrowing the age groups shows that opioid MMEs increased with age, starting at 49 MMEs for 18- to 26-year-olds and rising to a high of 856 MMEs in the 65- to 74-year-old group, before dropping off in the oldest adults, the investigators said in a Medical Expenditure Panel Survey (MEPS) research findings report.

The analysis included “all opioid medications that are commonly used to treat pain” and excluded respiratory agents, antitussives, and drugs used for medication-assisted treatment, they noted. The MEPS data cover prescriptions purchased or obtained in outpatient settings but not those administered in inpatient settings or in clinics or physician offices.

[email protected]

Patients with suspected migraine and a normal neurological examination without any atypical features or red flags do not need an MRI or CT, according to recent updated recommendations in a guideline released by the American Headache Society.

Migraine with atypical features may require neuroimaging, according to the guideline. These include an unusual aura; change in clinical features; a first or worst migraine; a migraine that presents with brainstem aura, confusion, or motor manifestation; migraine accompaniments in later life; headaches that are side-locked or posttraumatic; and aura that presents without headache.
 

Assessing the evidence

The recommendation to avoid MRI or CT in otherwise neurologically normal patients with migraine carried a grade A recommendation from the American Headache Society, while the specific considerations for neuroimaging was based on consensus and carried a grade C recommendation, according to lead author Randolph W. Evans, MD, of the department of neurology at Baylor College of Medicine in Houston, and colleagues.

The recommendations, published in the journal Headache (2020 Feb;60(2):318-36), came from a systematic review of 23 studies of adults at least 18 years old who underwent MRI or CT during outpatient treatment for migraine between 1973 and 2018. Ten studies looked at CT neuroimaging in patients with migraine, nine studies examined MRI neuroimaging alone in patients with migraine, and four studies contained adults with headache or migraine who underwent either MRI or CT. The majority of studies analyzed were retrospective or cross-sectional in nature, while four studies were prospective observational studies.

Dr. Evans and colleagues noted that neuroimaging for patients with suspected migraine is ordered for a variety of reasons, such as excluding conditions that aren’t migraine, diagnostic certainty, cognitive bias, practice workflow, medicolegal concerns, addressing patient and family anxiety, and addressing clinician anxiety. Neuroimaging also can be costly, they said, adding up to an estimated $1 billion annually according to one study, and can lead to additional testing from findings that may not be clinically significant.
 

Good advice, with caveats

In an interview, Alan M. Rapoport, MD, editor-in-chief of Neurology Reviews, said that while he generally does not like broad guideline recommendations, the recommendation made by the American Headache Society to avoid neuroimaging in patients with a normal neurological examination without any atypical features and red flags “takes most of the important factors into consideration and will work almost all the time.” The recommendation made by consensus for specific considerations of neuroimaging was issued by top headache specialists in the United States who reviewed the data, and it is unlikely a patient with a migraine as diagnosed by the International Classification of Headache Disorders with a normal neurological examination would have a significant abnormality that would appear with imaging, Dr. Rapoport said.

“If everyone caring for migraine patients knew these recommendations, and used them unless the patients fit the exclusions mentioned, we would have more efficient clinical practice and save lots of money on unnecessary scanning,” he said.

However, Dr. Rapoport, clinical professor of neurology at the University of California, Los Angeles, founder of the New England Center for Headache, and past president of The International Headache Society, said that not all clinicians will be convinced by the American Headache Society’s recommendations.

“Various third parties often jump on society recommendations or guidelines and prevent smart clinicians from doing what they need to do when they want to disregard the recommendation or guideline,” he explained. “More importantly, if a physician feels the need to think out of the box and image a patient without a clear reason, and the patient cannot pay for the scan when a medical insurance company refuses to authorize it, there can be a bad result if the patient does not get the study.”

Dr. Rapoport noted that the guideline does not address situations where neuroimaging may not pick up conditions that lead to migraine, such as a subarachnoid or subdural hemorrhage, reversible cerebral vasoconstriction syndrome, or early aspects of low cerebrospinal fluid pressure syndrome. Anxiety on the part of the patient or the clinician is another area that can be addressed by future research, he said.

“If the clinician does a good job of explaining the odds of anything significant being found with a typical migraine history and normal examination, and the patient says [they] need an MRI with contrast to be sure, it will be difficult to dissuade them,” said Dr. Rapoport. “If you don’t order one, they will find a way to get one. If it is abnormal, you could be in trouble. Also, if the clinician has no good reason to do a scan but has anxiety about what is being missed, it will probably get done.”

There was no funding source for the guidelines. The authors reported personal and institutional relationships in the form of advisory board memberships, investigator appointments, speakers bureau positions, research support, and consultancies for a variety of pharmaceutical companies, agencies, institutions, publishers, and other organizations.

Patients with suspected migraine and a normal neurological examination without any atypical features or red flags do not need an MRI or CT, according to recent updated recommendations in a guideline released by the American Headache Society.

Migraine with atypical features may require neuroimaging, according to the guideline. These include an unusual aura; change in clinical features; a first or worst migraine; a migraine that presents with brainstem aura, confusion, or motor manifestation; migraine accompaniments in later life; headaches that are side-locked or posttraumatic; and aura that presents without headache.
 

Assessing the evidence

The recommendation to avoid MRI or CT in otherwise neurologically normal patients with migraine carried a grade A recommendation from the American Headache Society, while the specific considerations for neuroimaging was based on consensus and carried a grade C recommendation, according to lead author Randolph W. Evans, MD, of the department of neurology at Baylor College of Medicine in Houston, and colleagues.

The recommendations, published in the journal Headache (2020 Feb;60(2):318-36), came from a systematic review of 23 studies of adults at least 18 years old who underwent MRI or CT during outpatient treatment for migraine between 1973 and 2018. Ten studies looked at CT neuroimaging in patients with migraine, nine studies examined MRI neuroimaging alone in patients with migraine, and four studies contained adults with headache or migraine who underwent either MRI or CT. The majority of studies analyzed were retrospective or cross-sectional in nature, while four studies were prospective observational studies.

Dr. Evans and colleagues noted that neuroimaging for patients with suspected migraine is ordered for a variety of reasons, such as excluding conditions that aren’t migraine, diagnostic certainty, cognitive bias, practice workflow, medicolegal concerns, addressing patient and family anxiety, and addressing clinician anxiety. Neuroimaging also can be costly, they said, adding up to an estimated $1 billion annually according to one study, and can lead to additional testing from findings that may not be clinically significant.
 

Good advice, with caveats

In an interview, Alan M. Rapoport, MD, editor-in-chief of Neurology Reviews, said that while he generally does not like broad guideline recommendations, the recommendation made by the American Headache Society to avoid neuroimaging in patients with a normal neurological examination without any atypical features and red flags “takes most of the important factors into consideration and will work almost all the time.” The recommendation made by consensus for specific considerations of neuroimaging was issued by top headache specialists in the United States who reviewed the data, and it is unlikely a patient with a migraine as diagnosed by the International Classification of Headache Disorders with a normal neurological examination would have a significant abnormality that would appear with imaging, Dr. Rapoport said.

“If everyone caring for migraine patients knew these recommendations, and used them unless the patients fit the exclusions mentioned, we would have more efficient clinical practice and save lots of money on unnecessary scanning,” he said.

However, Dr. Rapoport, clinical professor of neurology at the University of California, Los Angeles, founder of the New England Center for Headache, and past president of The International Headache Society, said that not all clinicians will be convinced by the American Headache Society’s recommendations.

“Various third parties often jump on society recommendations or guidelines and prevent smart clinicians from doing what they need to do when they want to disregard the recommendation or guideline,” he explained. “More importantly, if a physician feels the need to think out of the box and image a patient without a clear reason, and the patient cannot pay for the scan when a medical insurance company refuses to authorize it, there can be a bad result if the patient does not get the study.”

Dr. Rapoport noted that the guideline does not address situations where neuroimaging may not pick up conditions that lead to migraine, such as a subarachnoid or subdural hemorrhage, reversible cerebral vasoconstriction syndrome, or early aspects of low cerebrospinal fluid pressure syndrome. Anxiety on the part of the patient or the clinician is another area that can be addressed by future research, he said.

“If the clinician does a good job of explaining the odds of anything significant being found with a typical migraine history and normal examination, and the patient says [they] need an MRI with contrast to be sure, it will be difficult to dissuade them,” said Dr. Rapoport. “If you don’t order one, they will find a way to get one. If it is abnormal, you could be in trouble. Also, if the clinician has no good reason to do a scan but has anxiety about what is being missed, it will probably get done.”

There was no funding source for the guidelines. The authors reported personal and institutional relationships in the form of advisory board memberships, investigator appointments, speakers bureau positions, research support, and consultancies for a variety of pharmaceutical companies, agencies, institutions, publishers, and other organizations.

Patients with suspected migraine and a normal neurological examination without any atypical features or red flags do not need an MRI or CT, according to recent updated recommendations in a guideline released by the American Headache Society.

Migraine with atypical features may require neuroimaging, according to the guideline. These include an unusual aura; change in clinical features; a first or worst migraine; a migraine that presents with brainstem aura, confusion, or motor manifestation; migraine accompaniments in later life; headaches that are side-locked or posttraumatic; and aura that presents without headache.
 

Assessing the evidence

The recommendation to avoid MRI or CT in otherwise neurologically normal patients with migraine carried a grade A recommendation from the American Headache Society, while the specific considerations for neuroimaging was based on consensus and carried a grade C recommendation, according to lead author Randolph W. Evans, MD, of the department of neurology at Baylor College of Medicine in Houston, and colleagues.

The recommendations, published in the journal Headache (2020 Feb;60(2):318-36), came from a systematic review of 23 studies of adults at least 18 years old who underwent MRI or CT during outpatient treatment for migraine between 1973 and 2018. Ten studies looked at CT neuroimaging in patients with migraine, nine studies examined MRI neuroimaging alone in patients with migraine, and four studies contained adults with headache or migraine who underwent either MRI or CT. The majority of studies analyzed were retrospective or cross-sectional in nature, while four studies were prospective observational studies.

Dr. Evans and colleagues noted that neuroimaging for patients with suspected migraine is ordered for a variety of reasons, such as excluding conditions that aren’t migraine, diagnostic certainty, cognitive bias, practice workflow, medicolegal concerns, addressing patient and family anxiety, and addressing clinician anxiety. Neuroimaging also can be costly, they said, adding up to an estimated $1 billion annually according to one study, and can lead to additional testing from findings that may not be clinically significant.
 

Good advice, with caveats

In an interview, Alan M. Rapoport, MD, editor-in-chief of Neurology Reviews, said that while he generally does not like broad guideline recommendations, the recommendation made by the American Headache Society to avoid neuroimaging in patients with a normal neurological examination without any atypical features and red flags “takes most of the important factors into consideration and will work almost all the time.” The recommendation made by consensus for specific considerations of neuroimaging was issued by top headache specialists in the United States who reviewed the data, and it is unlikely a patient with a migraine as diagnosed by the International Classification of Headache Disorders with a normal neurological examination would have a significant abnormality that would appear with imaging, Dr. Rapoport said.

“If everyone caring for migraine patients knew these recommendations, and used them unless the patients fit the exclusions mentioned, we would have more efficient clinical practice and save lots of money on unnecessary scanning,” he said.

However, Dr. Rapoport, clinical professor of neurology at the University of California, Los Angeles, founder of the New England Center for Headache, and past president of The International Headache Society, said that not all clinicians will be convinced by the American Headache Society’s recommendations.

“Various third parties often jump on society recommendations or guidelines and prevent smart clinicians from doing what they need to do when they want to disregard the recommendation or guideline,” he explained. “More importantly, if a physician feels the need to think out of the box and image a patient without a clear reason, and the patient cannot pay for the scan when a medical insurance company refuses to authorize it, there can be a bad result if the patient does not get the study.”

Dr. Rapoport noted that the guideline does not address situations where neuroimaging may not pick up conditions that lead to migraine, such as a subarachnoid or subdural hemorrhage, reversible cerebral vasoconstriction syndrome, or early aspects of low cerebrospinal fluid pressure syndrome. Anxiety on the part of the patient or the clinician is another area that can be addressed by future research, he said.

“If the clinician does a good job of explaining the odds of anything significant being found with a typical migraine history and normal examination, and the patient says [they] need an MRI with contrast to be sure, it will be difficult to dissuade them,” said Dr. Rapoport. “If you don’t order one, they will find a way to get one. If it is abnormal, you could be in trouble. Also, if the clinician has no good reason to do a scan but has anxiety about what is being missed, it will probably get done.”

There was no funding source for the guidelines. The authors reported personal and institutional relationships in the form of advisory board memberships, investigator appointments, speakers bureau positions, research support, and consultancies for a variety of pharmaceutical companies, agencies, institutions, publishers, and other organizations.

NATIONAL HARBOR, MD. – Stimulation of the infrapatellar branch of the saphenous nerve with an implantable electrical device is a potentially effective treatment for chronic, intractable knee pain.

In a small case series consisting of five patients with chronic knee pain, pain intensity scores on the visual analog scale (VAS) dropped from an average of 8 out of 10 before the implant to 1.4 out of 10 when measured 6 months afterward.

Pain relief was also long lasting, with an average score at 2 years still significantly reduced from baseline, at 3 out of 10 on the VAS.

“We have a lot of patients with chronic knee pain, and unfortunately, our hands are tied in terms of what we can do for them,” lead author Kwo Wei David Ho, MD, PhD, Stanford University, California, told Medscape Medical News.

“They can use NSAIDs, physical therapy, some get steroid injections, or genicular nerve blocks, but they don’t work that well. Some have knee replacement surgery, and can still have persistent knee pain after the operation, so here we are using an alternative therapy called peripheral nerve stimulation of the saphenous nerve. This provides a way to relieve pain without nerve destruction or motor dysfunction,” Ho said.

The findings were presented here at the American Academy of Pain Medicine (AAPM) 2020 Annual Meeting.

Patient Controlled

For the study, the investigators surgically implanted five patients with intractable knee pain with the StimRouter™ (Bioness, Inc).

The device takes about 15 to 30 minutes to implant, much like a pacemaker, and reduces pain by delivering gentle electrical stimulation directly to a target peripheral nerve, in this case the saphenous nerve, to interrupt the pain signal, Ho said.

“A thin, threadlike lead, or noodle, is implanted below the skin next to the target peripheral nerve responsible for the pain signal under ultrasound guidance, and then a patch or external pulse transmitter (EPT) is worn on top of the skin. This sends electric stimulation through the skin to the lead,” he explained.

The patient can then control the EPT and adjust stimulation with a wireless handheld programmer.

“Some patients turn it on at night for a couple of hours and then turn it off, some leave it on for the entire night, or the whole day if they prefer. What we’ve been noticing in our series is that after a while, patients are using less and less, and the pain gets better and better, and eventually they stop using it entirely because the pain completely resolves,” Ho said.

Good candidates for this treatment are post-knee replacement patients with residual pain, he added.

Durable Effect

Of the five patients in the case series, four had previous knee arthroplasty.

To determine the chances of a good response to the implant, study participants underwent a diagnostic saphenous nerve block, with the rationale that if the block successfully reduced knee pain by 50% or more in the short term, patients would likely respond well to the implant.

Before the peripheral nerve stimulation implant, the average pain intensity was 7.8 out of 10 on the VAS. After stimulator implantation, the average pain intensity was 1.4 at 6 months (P = .019, in 5 patients). At 1 year, the average pain intensity score was virtually the same, at 1.5 on the VAS, (P = .0032, in 4 patients). At 2 years, the average pain intensity score was 2.75 (P = .12, in 2 patients).

“This study provides preliminary evidence that stimulation at the saphenous nerve may be effective for selected patients with chronic knee pain,” Ho said.

Commenting on the findings for Medscape Medical News, Patrick Tighe, MD, MS, University of Florida, Gainesville, said that chronic knee pain continues to present “numerous diagnostic and therapeutic challenges for many patients.”

“It may be surprising, but there is still so much we don’t know about the innervation of the knee, and we are still learning about different ways to alter the behavior of those nerves,” said Tighe, who was not involved with the current study.

“This work points to some exciting opportunities to help patients suffering from chronic knee pain. We certainly need more research in this area to figure out the optimal approach to applying these findings more widely,” he said.

Ho and Tighe have disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

NATIONAL HARBOR, MD. – Stimulation of the infrapatellar branch of the saphenous nerve with an implantable electrical device is a potentially effective treatment for chronic, intractable knee pain.

In a small case series consisting of five patients with chronic knee pain, pain intensity scores on the visual analog scale (VAS) dropped from an average of 8 out of 10 before the implant to 1.4 out of 10 when measured 6 months afterward.

Pain relief was also long lasting, with an average score at 2 years still significantly reduced from baseline, at 3 out of 10 on the VAS.

“We have a lot of patients with chronic knee pain, and unfortunately, our hands are tied in terms of what we can do for them,” lead author Kwo Wei David Ho, MD, PhD, Stanford University, California, told Medscape Medical News.

“They can use NSAIDs, physical therapy, some get steroid injections, or genicular nerve blocks, but they don’t work that well. Some have knee replacement surgery, and can still have persistent knee pain after the operation, so here we are using an alternative therapy called peripheral nerve stimulation of the saphenous nerve. This provides a way to relieve pain without nerve destruction or motor dysfunction,” Ho said.

The findings were presented here at the American Academy of Pain Medicine (AAPM) 2020 Annual Meeting.

Patient Controlled

For the study, the investigators surgically implanted five patients with intractable knee pain with the StimRouter™ (Bioness, Inc).

The device takes about 15 to 30 minutes to implant, much like a pacemaker, and reduces pain by delivering gentle electrical stimulation directly to a target peripheral nerve, in this case the saphenous nerve, to interrupt the pain signal, Ho said.

“A thin, threadlike lead, or noodle, is implanted below the skin next to the target peripheral nerve responsible for the pain signal under ultrasound guidance, and then a patch or external pulse transmitter (EPT) is worn on top of the skin. This sends electric stimulation through the skin to the lead,” he explained.

The patient can then control the EPT and adjust stimulation with a wireless handheld programmer.

“Some patients turn it on at night for a couple of hours and then turn it off, some leave it on for the entire night, or the whole day if they prefer. What we’ve been noticing in our series is that after a while, patients are using less and less, and the pain gets better and better, and eventually they stop using it entirely because the pain completely resolves,” Ho said.

Good candidates for this treatment are post-knee replacement patients with residual pain, he added.

Durable Effect

Of the five patients in the case series, four had previous knee arthroplasty.

To determine the chances of a good response to the implant, study participants underwent a diagnostic saphenous nerve block, with the rationale that if the block successfully reduced knee pain by 50% or more in the short term, patients would likely respond well to the implant.

Before the peripheral nerve stimulation implant, the average pain intensity was 7.8 out of 10 on the VAS. After stimulator implantation, the average pain intensity was 1.4 at 6 months (P = .019, in 5 patients). At 1 year, the average pain intensity score was virtually the same, at 1.5 on the VAS, (P = .0032, in 4 patients). At 2 years, the average pain intensity score was 2.75 (P = .12, in 2 patients).

“This study provides preliminary evidence that stimulation at the saphenous nerve may be effective for selected patients with chronic knee pain,” Ho said.

Commenting on the findings for Medscape Medical News, Patrick Tighe, MD, MS, University of Florida, Gainesville, said that chronic knee pain continues to present “numerous diagnostic and therapeutic challenges for many patients.”

“It may be surprising, but there is still so much we don’t know about the innervation of the knee, and we are still learning about different ways to alter the behavior of those nerves,” said Tighe, who was not involved with the current study.

“This work points to some exciting opportunities to help patients suffering from chronic knee pain. We certainly need more research in this area to figure out the optimal approach to applying these findings more widely,” he said.

Ho and Tighe have disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

NATIONAL HARBOR, MD. – Stimulation of the infrapatellar branch of the saphenous nerve with an implantable electrical device is a potentially effective treatment for chronic, intractable knee pain.

In a small case series consisting of five patients with chronic knee pain, pain intensity scores on the visual analog scale (VAS) dropped from an average of 8 out of 10 before the implant to 1.4 out of 10 when measured 6 months afterward.

Pain relief was also long lasting, with an average score at 2 years still significantly reduced from baseline, at 3 out of 10 on the VAS.

“We have a lot of patients with chronic knee pain, and unfortunately, our hands are tied in terms of what we can do for them,” lead author Kwo Wei David Ho, MD, PhD, Stanford University, California, told Medscape Medical News.

“They can use NSAIDs, physical therapy, some get steroid injections, or genicular nerve blocks, but they don’t work that well. Some have knee replacement surgery, and can still have persistent knee pain after the operation, so here we are using an alternative therapy called peripheral nerve stimulation of the saphenous nerve. This provides a way to relieve pain without nerve destruction or motor dysfunction,” Ho said.

The findings were presented here at the American Academy of Pain Medicine (AAPM) 2020 Annual Meeting.

Patient Controlled

For the study, the investigators surgically implanted five patients with intractable knee pain with the StimRouter™ (Bioness, Inc).

The device takes about 15 to 30 minutes to implant, much like a pacemaker, and reduces pain by delivering gentle electrical stimulation directly to a target peripheral nerve, in this case the saphenous nerve, to interrupt the pain signal, Ho said.

“A thin, threadlike lead, or noodle, is implanted below the skin next to the target peripheral nerve responsible for the pain signal under ultrasound guidance, and then a patch or external pulse transmitter (EPT) is worn on top of the skin. This sends electric stimulation through the skin to the lead,” he explained.

The patient can then control the EPT and adjust stimulation with a wireless handheld programmer.

“Some patients turn it on at night for a couple of hours and then turn it off, some leave it on for the entire night, or the whole day if they prefer. What we’ve been noticing in our series is that after a while, patients are using less and less, and the pain gets better and better, and eventually they stop using it entirely because the pain completely resolves,” Ho said.

Good candidates for this treatment are post-knee replacement patients with residual pain, he added.

Durable Effect

Of the five patients in the case series, four had previous knee arthroplasty.

To determine the chances of a good response to the implant, study participants underwent a diagnostic saphenous nerve block, with the rationale that if the block successfully reduced knee pain by 50% or more in the short term, patients would likely respond well to the implant.

Before the peripheral nerve stimulation implant, the average pain intensity was 7.8 out of 10 on the VAS. After stimulator implantation, the average pain intensity was 1.4 at 6 months (P = .019, in 5 patients). At 1 year, the average pain intensity score was virtually the same, at 1.5 on the VAS, (P = .0032, in 4 patients). At 2 years, the average pain intensity score was 2.75 (P = .12, in 2 patients).

“This study provides preliminary evidence that stimulation at the saphenous nerve may be effective for selected patients with chronic knee pain,” Ho said.

Commenting on the findings for Medscape Medical News, Patrick Tighe, MD, MS, University of Florida, Gainesville, said that chronic knee pain continues to present “numerous diagnostic and therapeutic challenges for many patients.”

“It may be surprising, but there is still so much we don’t know about the innervation of the knee, and we are still learning about different ways to alter the behavior of those nerves,” said Tighe, who was not involved with the current study.

“This work points to some exciting opportunities to help patients suffering from chronic knee pain. We certainly need more research in this area to figure out the optimal approach to applying these findings more widely,” he said.

Ho and Tighe have disclosed no relevant financial relationships.

This article first appeared on Medscape.com.