When the pain decreased, her troubles began

CASE: She’s not herself

Mrs. M, age 74, is brought to the ER by her husband after he finds her lying on their bedroom floor, incoherent and extremely drowsy. He reports that his wife, who suffers chronic arthritic back and joint pain, might have overdosed on pain medications.

According to her husband, Mrs. M has been taking combination oxycodone/acetaminophen and transdermal fentanyl at unknown dosages, but he is unsure when she started using these medications or if she is taking others. Serum toxicology screening shows twice the normal values for opioids and benzodiazepines; other laboratory results are normal.

Mrs. M is medically stable but her mental status is altered. She is oblivious to time, place and person, speaks to no one, and seems lost in her own world. The hospital’s medical service admits Mrs. M for stabilization and to determine whether the overdose was intentional.

Two days later, we evaluate Mrs. M’s mental status at the attending physician’s request. She appears confused and cannot answer our questions. Her husband tells us she was “doing fine” until approximately 4 months ago, when she started becoming increasingly forgetful and lethargic. He says she has been forgetting routine chores such as paying bills and grocery shopping. Recently, she has been getting lost during her evening walk; neighbors often help her find her way home.

Mrs. M has had no past psychiatric or medical problems but her husband says she has become increasingly suspicious and paranoid the past 2 months. After being happily married for 40 years, he says his wife now frequently accuses him of infidelity or stealing her possessions. Last week, she misplaced her medications and accused him of hiding them.

The authors’ observations

Two opioid medications—oxycodone/acetaminophen combination and transdermal fentanyl—are commonly used to manage moderate or severe pain from any type of chronic arthritis.

• Oxycodone, a semisynthetic opioid analgesic indicated for moderate to moderately severe pain, is used when nondrug measures and nonnarcotic medications do not control the pain.
  
• Transdermal fentanyl, a potent analgesic indicated for persistent moderate to severe chronic pain, typically is prescribed to patients who tolerate oral oxycodone, 30 mg/d; morphine, 60 mg; hydromorphone, 8 mg; or an equianalgesic dosage of another opioid for ≥1 week.
  

Mrs. M’s confusion and cloudy consciousness at admission strongly suggest delirium. Rapid opioid escalation can cause delirium,^1-3 but no preadmission laboratory work was done to affirm this.

Mrs. M also was taking a benzodiazepine, but which medication—and why she was taking it—were unclear. She had no psychiatric diagnosis, and her husband could not recall her medication history.

We also cannot explain Mrs. M’s negative cognitive and behavioral changes. Opioid overuse and onset of dementia-related cognitive decline are possibilities.

TRANSFER Why is she confused?

Based on information from the pharmacy department, doctors at the medical unit restart oxycodone/acetaminophen, 7.5/325 mg tid, and transdermal fentanyl, 25 mcg/hr every 3 days. After discussing how to treat Mrs. M, the psychiatric and medical services transfer her to the geriatric psychiatric inpatient unit 3 days after admission.

We visit Mrs. M hours after her transfer. She seems lethargic but not confused, although Mini-Mental State Examination (MMSE) score of 15 suggests moderate cognitive impairment. Vitamin B₁₂ and thyroid levels, erythrocyte sedimentation rate, and syphilis test results are normal, allowing us to rule out organic causes for her dementia. Brain MRI shows no neurologic damage. On a scale of 1 to 5 with 5 being most severe, Mrs. M scores her pain as 2 (mild) and her sedation as 3 (moderate).

Mrs. M acknowledges that on the day she collapsed, she might have forgotten she had taken oxycodone/acetaminophen and took it a second time. She then reveals she also had been taking “nerve pills” and might have taken more than usual that day. She says she has been feeling anxious about her forgetfulness and fears she is developing dementia, but she endorses no other current or past psychiatric symptoms.

With Mrs. M’s permission, we call her primary care physician for collateral information. The physician tells us Mrs. M has suffered severe joint pain for 2 years. Nonnarcotic medications and treatments—including counseling, support groups, massage, yoga, exercise, biofeedback, relaxation therapy, and physical therapy—were ineffective.

Approximately 10 months ago, the physician started oxycodone/acetaminophen at 2.5/325 mg bid and titrated it over 6 weeks to 7.5/325 mg tid for Mrs. M’s persistent joint pain. Four months ago, with her pain still severe, the physician added transdermal fentanyl, 25 mcg/hr every 3 days, after which the patient reported mild improvement.

 

One month after starting the fentanyl patch, Mrs. M complained of sudden forgetfulness, low energy, poor concentration, and increased sleep. The physician suspected depression with possible comorbid anxiety and prescribed sertraline, 50 mg/d, and alprazolam, 0.5 mg bid. Mrs. M stopped sertraline after 3 days because it was causing diarrhea but kept taking alprazolam.

Mrs. M saw her primary care physician once after starting alprazolam and sertraline but missed her most recent appointment last month. The physician says he inadvertently approved at least 1 premature request for an alprazolam refill.

Six days after admission, Mrs. M’s sedation, cognitive impairment, and lethargy persist. She reports no mood and anxiety problems, and we have not restarted alprazolam.

The authors’ observations

The fentanyl patch most likely began to diminish Mrs. M’s alertness soon after she started using it. The doctor, however, mistook cognitive slowing for new-onset depression or anxiety. Depressive symptoms can imitate dementia, but Mrs. M’s severe sedation and denial of depressive symptoms suggest a medication side effect.

The primary care physician’s reconstruction of Mrs. M’s history explained her positive benzodiazepine reading, and her use of the short-acting benzodiazepine alprazolam could account for her sudden-onset paranoia and cognitive decline (Box). Benzodiazepines can cause behavioral side effects such as disinhibition, agitation, or paranoia, and patients age ≥65 are at increased risk for these side effects.⁴ In particular, benzodiazepines with half-lives ≥6 to 8 hours such as clonazepam and oxazepam can cause short-term memory impairment, confusion, and delirium.^5-7

Box

Because alprazolam’s mean plasma half-life can be as short as 8 hours, 3 to 4 daily doses usually are necessary for day-long therapeutic effect. Multiple dosing of benzodiazepines, however, can cause withdrawal symptoms such as rebound anxiety and insomnia. To quell these symptoms, patients often take higher or additional benzodiazepine doses without a doctor’s permission, leading to potential overuse, addiction, or overdose.

When prescribing benzodiazepines (especially in older patients) watch for signs of overuse or abuse, such as early requests for refills, unkempt appearance, excessive sleepiness, or agitation (Table 1).

Table 1

Warning signs of opioid, benzodiazepine overuse

Frequent requests for early refills
Patient exceeds prescribed dosage without authorization
Patient reports lost/stolen prescription; if patient has history of substance abuse/dependence or legal problems, even 1 report should raise a red flag
Patient increasingly unkempt or impaired
Negative mood change
Agitation
Patient involved in car or other accidents
Sedation
Purposeful oversedation, particularly when patient has an apparent secondary gain from opioid use (such as qualifying for disability benefits or escaping from work)
New-onset cognitive impairment
Patient abusing alcohol or other illicit CNS depressants

The authors’ observations

Persistent chronic pain in the elderly can diminish health and quality of life, resulting in depression, social isolation, immobility, and sleep disturbance.

Managing an older patient’s pain can be challenging (Table 2). Opioids are effective painkillers, but even at relatively low dosages they can diminish function and cognition and increase risk of delirium. Also, patients’ ability to tolerate different opioids at different dosages varies widely.

Mrs. M’s opioid regimen was intolerable and numerous other treatments did not alleviate her pain. At this point, replacing fentanyl with another opioid was our best option.⁸

We decided to try methadone, which is indicated for moderate to severe pain that does not respond to nonnarcotic treatments. Methadone often is used for chronic pain associated with arthritis or malignancy.

Methadone is less sedating, more tolerable, and carries a lower risk of cognitive side effects than other opioids. Methadone also is fast- and long-acting—its analgesic effects begin within 30 minutes to 1 hour of oral administration⁹ and last approximately 12 hours, thus reducing the risk of breakthrough pain. Methadone also:

 

• has no active metabolites, which decreases the risk of hepatic side effects
  
• offers a high volume of distribution, thus allowing clinical effect with minimal dosing.
  

Oral methadone is a strong analgesic—20 mg is as potent as 100 mg of oral morphine. Start methadone at 5 to 10 mg bid or tid for chronic pain management and titrate according to clinical response and tolerability.^10-12

Beware the potential for addiction when prescribing opioids to any patient.^13,14 The U.S. Drug Enforcement Agency classifies both methadone and fentanyl as schedule II substances, which applies to highly addictive medications with FDA-approved indications. See patients at least biweekly, especially when switching or titrating pain medications, and watch closely for signs of overuse or addiction. Inform patients to:

• watch for symptoms such as oversedation, memory and concentration problems, and sudden changes in personality
  
• call you to clarify if these symptoms are methadone side effects.
  

Increase methadone by 5 mg every 3 to 4 days based on patient tolerance and response. If side effects decrease function or treatment response is lacking, consider a different opioid or another treatment. Decrease visit frequency to once monthly when the pain is under control and the patient experiences no side effects.

Watch for other potential side effects of methadone, such as constipation, sedation, breakthrough pain, sexual dysfunction, decreased immunity, respiratory depression, or prolonged corrected QT intervals.

Patients usually tolerate an immediate switch from transdermal fentanyl to methadone, but a sudden switch from high-dose fentanyl can reduce methadone’s effectiveness. Starting methadone at a high dosage to compensate for loss of effectiveness could increase side effect risk. If the fentanyl dosage exceeds 100 mcg/hr, taper by 25 mcg weekly. Simultaneously start methadone at a low dosage and titrate by 5 to 10 mg weekly as needed.

Table 2

Chronic pain management in the elderly: Dos and don’ts

DO
Use self rating scales, as patient can gauge his/her own pain most accurately
Consider nonpharmacologic treatments and nonnarcotic analgesics first
Watch closely for side effects and drug-drug/drug-disease interactions in patients receiving analgesics long-term
Monitor patients receiving opioids long-term for oversedation, changes in cognition and function
Consider switching to methadone or another opioid if patient cannot tolerate current opioid regimen
DO NOT
Prescribe propoxyphene or meperidine—which carry a higher risk of adverse effects than other opioids—to older patient
Prescribe opioids if the medical history is unclear
Increase opioid dosages without seeing the patient

TREATMENT Medication change

We stop transdermal fentanyl and start oral methadone, 5 mg bid, while continuing oxycodone/acetaminophen at the previous dosage.

Two days later, Mrs. M is much more alert. Since admission 1 week ago, her sedation rating has improved from 3 (mildly sedated) to 4 (almost fully alert). She rates her pain as mild and reports no breakthrough pain or other side effects from methadone. Her MMSE score has improved to 24—suggesting close to normal cognition—and she is much more interactive with staff and family.

Eight days after we start methadone, we stop oxycodone/acetaminophen and increase methadone to 10 mg bid to further improve cognition and alertness and to see if 1 pain medication is suffcient. Two days later, we discharge Mrs. M. She is fully alert, feels little or no joint pain, and is tolerating the methadone increase.

At outpatient follow-up 4 weeks later, Mrs. M remains pain-free and her MMSE score is 29, suggesting normal cognition. Over 8 months, we continue to see her monthly and then bi-monthly, after which we refer her to her primary care physician.

Related resources

• American Association for Geriatric Psychiatry. www.aagponline.org.
  
• American Pain Society. www.ampainsoc.org.
  

Drug brand names

• Alprazolam • Xanax
  
• Clonazepam • Klonopin
  
• Fentanyl (transdermal) • Duragesic
  
• Hydromorphone • Dilaudid
  
• Meperidine • Demerol
  
• Methadone • Dolophine
  
• Oxazepam • Serax
  
• Oxycodone • OxyContin, Roxicodone
  
• Oxycodone/acetaminophen • Percocet
  
• Propoxyphene • Darvon
  
• Sertraline • Zoloft
  

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

CASE: She’s not herself

Mrs. M, age 74, is brought to the ER by her husband after he finds her lying on their bedroom floor, incoherent and extremely drowsy. He reports that his wife, who suffers chronic arthritic back and joint pain, might have overdosed on pain medications.

According to her husband, Mrs. M has been taking combination oxycodone/acetaminophen and transdermal fentanyl at unknown dosages, but he is unsure when she started using these medications or if she is taking others. Serum toxicology screening shows twice the normal values for opioids and benzodiazepines; other laboratory results are normal.

Mrs. M is medically stable but her mental status is altered. She is oblivious to time, place and person, speaks to no one, and seems lost in her own world. The hospital’s medical service admits Mrs. M for stabilization and to determine whether the overdose was intentional.

Two days later, we evaluate Mrs. M’s mental status at the attending physician’s request. She appears confused and cannot answer our questions. Her husband tells us she was “doing fine” until approximately 4 months ago, when she started becoming increasingly forgetful and lethargic. He says she has been forgetting routine chores such as paying bills and grocery shopping. Recently, she has been getting lost during her evening walk; neighbors often help her find her way home.

Mrs. M has had no past psychiatric or medical problems but her husband says she has become increasingly suspicious and paranoid the past 2 months. After being happily married for 40 years, he says his wife now frequently accuses him of infidelity or stealing her possessions. Last week, she misplaced her medications and accused him of hiding them.

The authors’ observations

Two opioid medications—oxycodone/acetaminophen combination and transdermal fentanyl—are commonly used to manage moderate or severe pain from any type of chronic arthritis.

• Oxycodone, a semisynthetic opioid analgesic indicated for moderate to moderately severe pain, is used when nondrug measures and nonnarcotic medications do not control the pain.
  
• Transdermal fentanyl, a potent analgesic indicated for persistent moderate to severe chronic pain, typically is prescribed to patients who tolerate oral oxycodone, 30 mg/d; morphine, 60 mg; hydromorphone, 8 mg; or an equianalgesic dosage of another opioid for ≥1 week.
  

Mrs. M’s confusion and cloudy consciousness at admission strongly suggest delirium. Rapid opioid escalation can cause delirium,^1-3 but no preadmission laboratory work was done to affirm this.

Mrs. M also was taking a benzodiazepine, but which medication—and why she was taking it—were unclear. She had no psychiatric diagnosis, and her husband could not recall her medication history.

We also cannot explain Mrs. M’s negative cognitive and behavioral changes. Opioid overuse and onset of dementia-related cognitive decline are possibilities.

TRANSFER Why is she confused?

Based on information from the pharmacy department, doctors at the medical unit restart oxycodone/acetaminophen, 7.5/325 mg tid, and transdermal fentanyl, 25 mcg/hr every 3 days. After discussing how to treat Mrs. M, the psychiatric and medical services transfer her to the geriatric psychiatric inpatient unit 3 days after admission.

We visit Mrs. M hours after her transfer. She seems lethargic but not confused, although Mini-Mental State Examination (MMSE) score of 15 suggests moderate cognitive impairment. Vitamin B₁₂ and thyroid levels, erythrocyte sedimentation rate, and syphilis test results are normal, allowing us to rule out organic causes for her dementia. Brain MRI shows no neurologic damage. On a scale of 1 to 5 with 5 being most severe, Mrs. M scores her pain as 2 (mild) and her sedation as 3 (moderate).

Mrs. M acknowledges that on the day she collapsed, she might have forgotten she had taken oxycodone/acetaminophen and took it a second time. She then reveals she also had been taking “nerve pills” and might have taken more than usual that day. She says she has been feeling anxious about her forgetfulness and fears she is developing dementia, but she endorses no other current or past psychiatric symptoms.

With Mrs. M’s permission, we call her primary care physician for collateral information. The physician tells us Mrs. M has suffered severe joint pain for 2 years. Nonnarcotic medications and treatments—including counseling, support groups, massage, yoga, exercise, biofeedback, relaxation therapy, and physical therapy—were ineffective.

Approximately 10 months ago, the physician started oxycodone/acetaminophen at 2.5/325 mg bid and titrated it over 6 weeks to 7.5/325 mg tid for Mrs. M’s persistent joint pain. Four months ago, with her pain still severe, the physician added transdermal fentanyl, 25 mcg/hr every 3 days, after which the patient reported mild improvement.

 

One month after starting the fentanyl patch, Mrs. M complained of sudden forgetfulness, low energy, poor concentration, and increased sleep. The physician suspected depression with possible comorbid anxiety and prescribed sertraline, 50 mg/d, and alprazolam, 0.5 mg bid. Mrs. M stopped sertraline after 3 days because it was causing diarrhea but kept taking alprazolam.

Mrs. M saw her primary care physician once after starting alprazolam and sertraline but missed her most recent appointment last month. The physician says he inadvertently approved at least 1 premature request for an alprazolam refill.

Six days after admission, Mrs. M’s sedation, cognitive impairment, and lethargy persist. She reports no mood and anxiety problems, and we have not restarted alprazolam.

The authors’ observations

The fentanyl patch most likely began to diminish Mrs. M’s alertness soon after she started using it. The doctor, however, mistook cognitive slowing for new-onset depression or anxiety. Depressive symptoms can imitate dementia, but Mrs. M’s severe sedation and denial of depressive symptoms suggest a medication side effect.

The primary care physician’s reconstruction of Mrs. M’s history explained her positive benzodiazepine reading, and her use of the short-acting benzodiazepine alprazolam could account for her sudden-onset paranoia and cognitive decline (Box). Benzodiazepines can cause behavioral side effects such as disinhibition, agitation, or paranoia, and patients age ≥65 are at increased risk for these side effects.⁴ In particular, benzodiazepines with half-lives ≥6 to 8 hours such as clonazepam and oxazepam can cause short-term memory impairment, confusion, and delirium.^5-7

Box

Because alprazolam’s mean plasma half-life can be as short as 8 hours, 3 to 4 daily doses usually are necessary for day-long therapeutic effect. Multiple dosing of benzodiazepines, however, can cause withdrawal symptoms such as rebound anxiety and insomnia. To quell these symptoms, patients often take higher or additional benzodiazepine doses without a doctor’s permission, leading to potential overuse, addiction, or overdose.

When prescribing benzodiazepines (especially in older patients) watch for signs of overuse or abuse, such as early requests for refills, unkempt appearance, excessive sleepiness, or agitation (Table 1).

Table 1

Warning signs of opioid, benzodiazepine overuse

Frequent requests for early refills
Patient exceeds prescribed dosage without authorization
Patient reports lost/stolen prescription; if patient has history of substance abuse/dependence or legal problems, even 1 report should raise a red flag
Patient increasingly unkempt or impaired
Negative mood change
Agitation
Patient involved in car or other accidents
Sedation
Purposeful oversedation, particularly when patient has an apparent secondary gain from opioid use (such as qualifying for disability benefits or escaping from work)
New-onset cognitive impairment
Patient abusing alcohol or other illicit CNS depressants

The authors’ observations

Persistent chronic pain in the elderly can diminish health and quality of life, resulting in depression, social isolation, immobility, and sleep disturbance.

Managing an older patient’s pain can be challenging (Table 2). Opioids are effective painkillers, but even at relatively low dosages they can diminish function and cognition and increase risk of delirium. Also, patients’ ability to tolerate different opioids at different dosages varies widely.

Mrs. M’s opioid regimen was intolerable and numerous other treatments did not alleviate her pain. At this point, replacing fentanyl with another opioid was our best option.⁸

We decided to try methadone, which is indicated for moderate to severe pain that does not respond to nonnarcotic treatments. Methadone often is used for chronic pain associated with arthritis or malignancy.

Methadone is less sedating, more tolerable, and carries a lower risk of cognitive side effects than other opioids. Methadone also is fast- and long-acting—its analgesic effects begin within 30 minutes to 1 hour of oral administration⁹ and last approximately 12 hours, thus reducing the risk of breakthrough pain. Methadone also:

 

• has no active metabolites, which decreases the risk of hepatic side effects
  
• offers a high volume of distribution, thus allowing clinical effect with minimal dosing.
  

Oral methadone is a strong analgesic—20 mg is as potent as 100 mg of oral morphine. Start methadone at 5 to 10 mg bid or tid for chronic pain management and titrate according to clinical response and tolerability.^10-12

Beware the potential for addiction when prescribing opioids to any patient.^13,14 The U.S. Drug Enforcement Agency classifies both methadone and fentanyl as schedule II substances, which applies to highly addictive medications with FDA-approved indications. See patients at least biweekly, especially when switching or titrating pain medications, and watch closely for signs of overuse or addiction. Inform patients to:

• watch for symptoms such as oversedation, memory and concentration problems, and sudden changes in personality
  
• call you to clarify if these symptoms are methadone side effects.
  

Increase methadone by 5 mg every 3 to 4 days based on patient tolerance and response. If side effects decrease function or treatment response is lacking, consider a different opioid or another treatment. Decrease visit frequency to once monthly when the pain is under control and the patient experiences no side effects.

Watch for other potential side effects of methadone, such as constipation, sedation, breakthrough pain, sexual dysfunction, decreased immunity, respiratory depression, or prolonged corrected QT intervals.

Patients usually tolerate an immediate switch from transdermal fentanyl to methadone, but a sudden switch from high-dose fentanyl can reduce methadone’s effectiveness. Starting methadone at a high dosage to compensate for loss of effectiveness could increase side effect risk. If the fentanyl dosage exceeds 100 mcg/hr, taper by 25 mcg weekly. Simultaneously start methadone at a low dosage and titrate by 5 to 10 mg weekly as needed.

Table 2

Chronic pain management in the elderly: Dos and don’ts

DO
Use self rating scales, as patient can gauge his/her own pain most accurately
Consider nonpharmacologic treatments and nonnarcotic analgesics first
Watch closely for side effects and drug-drug/drug-disease interactions in patients receiving analgesics long-term
Monitor patients receiving opioids long-term for oversedation, changes in cognition and function
Consider switching to methadone or another opioid if patient cannot tolerate current opioid regimen
DO NOT
Prescribe propoxyphene or meperidine—which carry a higher risk of adverse effects than other opioids—to older patient
Prescribe opioids if the medical history is unclear
Increase opioid dosages without seeing the patient

TREATMENT Medication change

We stop transdermal fentanyl and start oral methadone, 5 mg bid, while continuing oxycodone/acetaminophen at the previous dosage.

Two days later, Mrs. M is much more alert. Since admission 1 week ago, her sedation rating has improved from 3 (mildly sedated) to 4 (almost fully alert). She rates her pain as mild and reports no breakthrough pain or other side effects from methadone. Her MMSE score has improved to 24—suggesting close to normal cognition—and she is much more interactive with staff and family.

Eight days after we start methadone, we stop oxycodone/acetaminophen and increase methadone to 10 mg bid to further improve cognition and alertness and to see if 1 pain medication is suffcient. Two days later, we discharge Mrs. M. She is fully alert, feels little or no joint pain, and is tolerating the methadone increase.

At outpatient follow-up 4 weeks later, Mrs. M remains pain-free and her MMSE score is 29, suggesting normal cognition. Over 8 months, we continue to see her monthly and then bi-monthly, after which we refer her to her primary care physician.

Related resources

• American Association for Geriatric Psychiatry. www.aagponline.org.
  
• American Pain Society. www.ampainsoc.org.
  

Drug brand names

• Alprazolam • Xanax
  
• Clonazepam • Klonopin
  
• Fentanyl (transdermal) • Duragesic
  
• Hydromorphone • Dilaudid
  
• Meperidine • Demerol
  
• Methadone • Dolophine
  
• Oxazepam • Serax
  
• Oxycodone • OxyContin, Roxicodone
  
• Oxycodone/acetaminophen • Percocet
  
• Propoxyphene • Darvon
  
• Sertraline • Zoloft
  

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

CASE: She’s not herself

Mrs. M, age 74, is brought to the ER by her husband after he finds her lying on their bedroom floor, incoherent and extremely drowsy. He reports that his wife, who suffers chronic arthritic back and joint pain, might have overdosed on pain medications.

According to her husband, Mrs. M has been taking combination oxycodone/acetaminophen and transdermal fentanyl at unknown dosages, but he is unsure when she started using these medications or if she is taking others. Serum toxicology screening shows twice the normal values for opioids and benzodiazepines; other laboratory results are normal.

Mrs. M is medically stable but her mental status is altered. She is oblivious to time, place and person, speaks to no one, and seems lost in her own world. The hospital’s medical service admits Mrs. M for stabilization and to determine whether the overdose was intentional.

Two days later, we evaluate Mrs. M’s mental status at the attending physician’s request. She appears confused and cannot answer our questions. Her husband tells us she was “doing fine” until approximately 4 months ago, when she started becoming increasingly forgetful and lethargic. He says she has been forgetting routine chores such as paying bills and grocery shopping. Recently, she has been getting lost during her evening walk; neighbors often help her find her way home.

Mrs. M has had no past psychiatric or medical problems but her husband says she has become increasingly suspicious and paranoid the past 2 months. After being happily married for 40 years, he says his wife now frequently accuses him of infidelity or stealing her possessions. Last week, she misplaced her medications and accused him of hiding them.

The authors’ observations

Two opioid medications—oxycodone/acetaminophen combination and transdermal fentanyl—are commonly used to manage moderate or severe pain from any type of chronic arthritis.

• Oxycodone, a semisynthetic opioid analgesic indicated for moderate to moderately severe pain, is used when nondrug measures and nonnarcotic medications do not control the pain.
  
• Transdermal fentanyl, a potent analgesic indicated for persistent moderate to severe chronic pain, typically is prescribed to patients who tolerate oral oxycodone, 30 mg/d; morphine, 60 mg; hydromorphone, 8 mg; or an equianalgesic dosage of another opioid for ≥1 week.
  

Mrs. M’s confusion and cloudy consciousness at admission strongly suggest delirium. Rapid opioid escalation can cause delirium,^1-3 but no preadmission laboratory work was done to affirm this.

Mrs. M also was taking a benzodiazepine, but which medication—and why she was taking it—were unclear. She had no psychiatric diagnosis, and her husband could not recall her medication history.

We also cannot explain Mrs. M’s negative cognitive and behavioral changes. Opioid overuse and onset of dementia-related cognitive decline are possibilities.

TRANSFER Why is she confused?

Based on information from the pharmacy department, doctors at the medical unit restart oxycodone/acetaminophen, 7.5/325 mg tid, and transdermal fentanyl, 25 mcg/hr every 3 days. After discussing how to treat Mrs. M, the psychiatric and medical services transfer her to the geriatric psychiatric inpatient unit 3 days after admission.

We visit Mrs. M hours after her transfer. She seems lethargic but not confused, although Mini-Mental State Examination (MMSE) score of 15 suggests moderate cognitive impairment. Vitamin B₁₂ and thyroid levels, erythrocyte sedimentation rate, and syphilis test results are normal, allowing us to rule out organic causes for her dementia. Brain MRI shows no neurologic damage. On a scale of 1 to 5 with 5 being most severe, Mrs. M scores her pain as 2 (mild) and her sedation as 3 (moderate).

Mrs. M acknowledges that on the day she collapsed, she might have forgotten she had taken oxycodone/acetaminophen and took it a second time. She then reveals she also had been taking “nerve pills” and might have taken more than usual that day. She says she has been feeling anxious about her forgetfulness and fears she is developing dementia, but she endorses no other current or past psychiatric symptoms.

With Mrs. M’s permission, we call her primary care physician for collateral information. The physician tells us Mrs. M has suffered severe joint pain for 2 years. Nonnarcotic medications and treatments—including counseling, support groups, massage, yoga, exercise, biofeedback, relaxation therapy, and physical therapy—were ineffective.

Approximately 10 months ago, the physician started oxycodone/acetaminophen at 2.5/325 mg bid and titrated it over 6 weeks to 7.5/325 mg tid for Mrs. M’s persistent joint pain. Four months ago, with her pain still severe, the physician added transdermal fentanyl, 25 mcg/hr every 3 days, after which the patient reported mild improvement.

 

One month after starting the fentanyl patch, Mrs. M complained of sudden forgetfulness, low energy, poor concentration, and increased sleep. The physician suspected depression with possible comorbid anxiety and prescribed sertraline, 50 mg/d, and alprazolam, 0.5 mg bid. Mrs. M stopped sertraline after 3 days because it was causing diarrhea but kept taking alprazolam.

Mrs. M saw her primary care physician once after starting alprazolam and sertraline but missed her most recent appointment last month. The physician says he inadvertently approved at least 1 premature request for an alprazolam refill.

Six days after admission, Mrs. M’s sedation, cognitive impairment, and lethargy persist. She reports no mood and anxiety problems, and we have not restarted alprazolam.

The authors’ observations

The fentanyl patch most likely began to diminish Mrs. M’s alertness soon after she started using it. The doctor, however, mistook cognitive slowing for new-onset depression or anxiety. Depressive symptoms can imitate dementia, but Mrs. M’s severe sedation and denial of depressive symptoms suggest a medication side effect.

The primary care physician’s reconstruction of Mrs. M’s history explained her positive benzodiazepine reading, and her use of the short-acting benzodiazepine alprazolam could account for her sudden-onset paranoia and cognitive decline (Box). Benzodiazepines can cause behavioral side effects such as disinhibition, agitation, or paranoia, and patients age ≥65 are at increased risk for these side effects.⁴ In particular, benzodiazepines with half-lives ≥6 to 8 hours such as clonazepam and oxazepam can cause short-term memory impairment, confusion, and delirium.^5-7

Box

Because alprazolam’s mean plasma half-life can be as short as 8 hours, 3 to 4 daily doses usually are necessary for day-long therapeutic effect. Multiple dosing of benzodiazepines, however, can cause withdrawal symptoms such as rebound anxiety and insomnia. To quell these symptoms, patients often take higher or additional benzodiazepine doses without a doctor’s permission, leading to potential overuse, addiction, or overdose.

When prescribing benzodiazepines (especially in older patients) watch for signs of overuse or abuse, such as early requests for refills, unkempt appearance, excessive sleepiness, or agitation (Table 1).

Table 1

Warning signs of opioid, benzodiazepine overuse

Frequent requests for early refills
Patient exceeds prescribed dosage without authorization
Patient reports lost/stolen prescription; if patient has history of substance abuse/dependence or legal problems, even 1 report should raise a red flag
Patient increasingly unkempt or impaired
Negative mood change
Agitation
Patient involved in car or other accidents
Sedation
Purposeful oversedation, particularly when patient has an apparent secondary gain from opioid use (such as qualifying for disability benefits or escaping from work)
New-onset cognitive impairment
Patient abusing alcohol or other illicit CNS depressants

The authors’ observations

Persistent chronic pain in the elderly can diminish health and quality of life, resulting in depression, social isolation, immobility, and sleep disturbance.

Managing an older patient’s pain can be challenging (Table 2). Opioids are effective painkillers, but even at relatively low dosages they can diminish function and cognition and increase risk of delirium. Also, patients’ ability to tolerate different opioids at different dosages varies widely.

Mrs. M’s opioid regimen was intolerable and numerous other treatments did not alleviate her pain. At this point, replacing fentanyl with another opioid was our best option.⁸

We decided to try methadone, which is indicated for moderate to severe pain that does not respond to nonnarcotic treatments. Methadone often is used for chronic pain associated with arthritis or malignancy.

Methadone is less sedating, more tolerable, and carries a lower risk of cognitive side effects than other opioids. Methadone also is fast- and long-acting—its analgesic effects begin within 30 minutes to 1 hour of oral administration⁹ and last approximately 12 hours, thus reducing the risk of breakthrough pain. Methadone also:

 

• has no active metabolites, which decreases the risk of hepatic side effects
  
• offers a high volume of distribution, thus allowing clinical effect with minimal dosing.
  

Oral methadone is a strong analgesic—20 mg is as potent as 100 mg of oral morphine. Start methadone at 5 to 10 mg bid or tid for chronic pain management and titrate according to clinical response and tolerability.^10-12

Beware the potential for addiction when prescribing opioids to any patient.^13,14 The U.S. Drug Enforcement Agency classifies both methadone and fentanyl as schedule II substances, which applies to highly addictive medications with FDA-approved indications. See patients at least biweekly, especially when switching or titrating pain medications, and watch closely for signs of overuse or addiction. Inform patients to:

• watch for symptoms such as oversedation, memory and concentration problems, and sudden changes in personality
  
• call you to clarify if these symptoms are methadone side effects.
  

Increase methadone by 5 mg every 3 to 4 days based on patient tolerance and response. If side effects decrease function or treatment response is lacking, consider a different opioid or another treatment. Decrease visit frequency to once monthly when the pain is under control and the patient experiences no side effects.

Watch for other potential side effects of methadone, such as constipation, sedation, breakthrough pain, sexual dysfunction, decreased immunity, respiratory depression, or prolonged corrected QT intervals.

Patients usually tolerate an immediate switch from transdermal fentanyl to methadone, but a sudden switch from high-dose fentanyl can reduce methadone’s effectiveness. Starting methadone at a high dosage to compensate for loss of effectiveness could increase side effect risk. If the fentanyl dosage exceeds 100 mcg/hr, taper by 25 mcg weekly. Simultaneously start methadone at a low dosage and titrate by 5 to 10 mg weekly as needed.

Table 2

Chronic pain management in the elderly: Dos and don’ts

DO
Use self rating scales, as patient can gauge his/her own pain most accurately
Consider nonpharmacologic treatments and nonnarcotic analgesics first
Watch closely for side effects and drug-drug/drug-disease interactions in patients receiving analgesics long-term
Monitor patients receiving opioids long-term for oversedation, changes in cognition and function
Consider switching to methadone or another opioid if patient cannot tolerate current opioid regimen
DO NOT
Prescribe propoxyphene or meperidine—which carry a higher risk of adverse effects than other opioids—to older patient
Prescribe opioids if the medical history is unclear
Increase opioid dosages without seeing the patient

TREATMENT Medication change

We stop transdermal fentanyl and start oral methadone, 5 mg bid, while continuing oxycodone/acetaminophen at the previous dosage.

Two days later, Mrs. M is much more alert. Since admission 1 week ago, her sedation rating has improved from 3 (mildly sedated) to 4 (almost fully alert). She rates her pain as mild and reports no breakthrough pain or other side effects from methadone. Her MMSE score has improved to 24—suggesting close to normal cognition—and she is much more interactive with staff and family.

Eight days after we start methadone, we stop oxycodone/acetaminophen and increase methadone to 10 mg bid to further improve cognition and alertness and to see if 1 pain medication is suffcient. Two days later, we discharge Mrs. M. She is fully alert, feels little or no joint pain, and is tolerating the methadone increase.

At outpatient follow-up 4 weeks later, Mrs. M remains pain-free and her MMSE score is 29, suggesting normal cognition. Over 8 months, we continue to see her monthly and then bi-monthly, after which we refer her to her primary care physician.

Related resources

• American Association for Geriatric Psychiatry. www.aagponline.org.
  
• American Pain Society. www.ampainsoc.org.
  

Drug brand names

• Alprazolam • Xanax
  
• Clonazepam • Klonopin
  
• Fentanyl (transdermal) • Duragesic
  
• Hydromorphone • Dilaudid
  
• Meperidine • Demerol
  
• Methadone • Dolophine
  
• Oxazepam • Serax
  
• Oxycodone • OxyContin, Roxicodone
  
• Oxycodone/acetaminophen • Percocet
  
• Propoxyphene • Darvon
  
• Sertraline • Zoloft
  

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.