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Time to Reconsider Tramadol for Chronic Pain?
Time to Reconsider Tramadol for Chronic Pain?
Tramadol, a commonly prescribed opioid often viewed as a safer option for chronic pain, provided limited pain relief while increasing the risk for serious adverse effects, results of a new analysis showed.
In a systematic review and meta-analysis, investigators found that tramadol offered clinically insignificant pain relief, while doubling the likelihood of serious adverse events, most commonly cardiac complications.
"Given the limited analgesic benefits and increased risk of harm, tramadol use for chronic pain should be reconsidered," Jehad Ahmad Barakji, MD, of the Centre for Clinical Intervention Research at Rigshospitalet in Copenhagen, Denmark, told Medscape Medical News.
"Across different chronic pain conditions, tramadol's pain-relieving effect appears modest, and while some patients may experience relief, most will not gain substantial benefit," he added.
However, the researchers cautioned that the certainty of the evidence was low-to-moderate and that the quality of the underlying trials varied substantially.
The study was published on October 7 in BMJ Evidence-Based Medicine.
Popularity Outpacing Proof
Tramadol, a dual-action opioid that modulates serotonin and norepinephrine pathways, has long been promoted as a middle-ground analgesic - less addictive than morphine but stronger than nonopioid medications. It is approved for moderate-to-severe pain, including postoperative and chronic conditions.
Prescriptions have risen sharply worldwide, fueled by perceptions of safety and a belief that tramadol carries a lower risk for dependence. A recent global analysis estimated that nearly 18% of adults have used tramadol in their lifetime, and > 80% of those users combined it with at least 1 other substance.
Despite its widespread use, evidence supporting tramadol's long-term effectiveness and safety in chronic pain has been limited and inconsistent. Previous research has largely focused on short-term or condition-specific outcomes, such as osteoarthritis or neuropathic pain, leaving uncertainty about the drug's overall risk-benefit profile.
Small Benefit, Big Risk
The current study is the first comprehensive systematic review to evaluate tramadol alone for chronic pain using both meta-analysis and trail sequential analysis, provided a broader view of efficacy and safety across pain types.
"We sought to fill this gap by evaluating the totality of evidence to guide clinical practice," Barakji said.
The analysis included 19 randomized, placebo-controlled trials with 6569 adults. The average participant age was 56 years, and study durations ranged from 4 to 16 weeks. Pain intensity was typically assessed with the 0-10 numeric rating scale (NRS), while function and quality of life were measured with validated patient-reported tools.
Across the pooled analysis, participants receiving tramadol experienced an average pain reduction of 0.9 points on the NRS compared with placebo - a difference below the 1-point threshold considered clinically meaningful. About 7% more patients in the tramadol groups achieved noticeable pain relief, but investigators said the benefit was modest and uncertain.
Serious adverse events were twice as common among tramadol users, most often involving cardiac complications such as chest pain, coronary artery disease, or heart failure. Nonserious adverse effects, including nausea, dizziness, constipation, and drowsiness, were frequent and contributed to higher discontinuation rates among tramadol recipients.
The researchers acknowledged that most included trials were at a high risk for bias due to incomplete outcome reporting, small sample sizes, and inconsistent assessment methods, factors that may have exaggerated benefits and underestimated harms.
Reevaluating Tramadol's Role
Commenting on the research, Jessica Otte, MD, clinical associate professor in the Department of Family Medicine at The University of British Columbia, Vancouver, British Columbia, Canada, said the new review stands out for examining tramadol's use across a range of chronic pain conditions, an area where clinicians often struggle to help patients achieve meaningful and sustained relief.
Otte, who has studied the drug's safety and effectiveness through The University of British Columbia's Therapeutics Initiative, said the Danish team's analysis expands on earlier research that largely focused on single pain conditions. The findings, she said, add weight to growing evidence that challenges tramadol's perceived advantages over other analgesics.
"This review doesn't change the narrative but strengthens it: Tramdol's reputation as a safer or uniquely effective opioid is increasingly difficult to defend," she told Medscape Medical News.
While she believes the study makes an important contribution, Otte said the results should be interpreted with caution because of gaps in the underlying evidence. The Danish authors noted similar concerns, and Otte agreed that many of the included trials had methodological shortcomings.
"A lot of the studies had biases that made use less certain about what was reported," she said. "Many outcomes that matter to patients - like quality of life, functional improvement, or withdrawal - were either inconsistently measured or not reported at all."
She added that patients assigned to tramadol were more likely to discontinue early, both overall and because of adverse effects, raising concern about tolerability and attrition bias.
Also commenting, Houman Danesh, MD, professor and medical director of pain management at the Icahn School of Medicine at Mount Sinai in New York City, said the review provides moderate-certainty evidence that tramadol increases the risk for serious adverse events; but its broad approach - evaluating efficacy and safety across multiple chronic pain conditions - could be a confounding factor.
"Tramadol may benefit some conditions more than others," he noted, which could alter the overall risk-benefit profile.
In his clinical experience, Danesh said severe complications such as cardiac events are uncommon. He explained that heart rhythm disturbances occasionally associated with tramadol generally arise when patients are taking other medications that affect cardiac conduction.
Danesh emphasized that clinicians should weigh the study alongside other research and their own experience when deciding whether to prescribe the drug.
"It's important to take this study into consideration," he said, "but there are multiple studies that support the use of tramadol, and we have to look at the totality of the evidence."
Written by Carla Cantor.
The authors declared no competing interests and received no specific grant from any funding agency. Otte and Danesh reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Tramadol, a commonly prescribed opioid often viewed as a safer option for chronic pain, provided limited pain relief while increasing the risk for serious adverse effects, results of a new analysis showed.
In a systematic review and meta-analysis, investigators found that tramadol offered clinically insignificant pain relief, while doubling the likelihood of serious adverse events, most commonly cardiac complications.
"Given the limited analgesic benefits and increased risk of harm, tramadol use for chronic pain should be reconsidered," Jehad Ahmad Barakji, MD, of the Centre for Clinical Intervention Research at Rigshospitalet in Copenhagen, Denmark, told Medscape Medical News.
"Across different chronic pain conditions, tramadol's pain-relieving effect appears modest, and while some patients may experience relief, most will not gain substantial benefit," he added.
However, the researchers cautioned that the certainty of the evidence was low-to-moderate and that the quality of the underlying trials varied substantially.
The study was published on October 7 in BMJ Evidence-Based Medicine.
Popularity Outpacing Proof
Tramadol, a dual-action opioid that modulates serotonin and norepinephrine pathways, has long been promoted as a middle-ground analgesic - less addictive than morphine but stronger than nonopioid medications. It is approved for moderate-to-severe pain, including postoperative and chronic conditions.
Prescriptions have risen sharply worldwide, fueled by perceptions of safety and a belief that tramadol carries a lower risk for dependence. A recent global analysis estimated that nearly 18% of adults have used tramadol in their lifetime, and > 80% of those users combined it with at least 1 other substance.
Despite its widespread use, evidence supporting tramadol's long-term effectiveness and safety in chronic pain has been limited and inconsistent. Previous research has largely focused on short-term or condition-specific outcomes, such as osteoarthritis or neuropathic pain, leaving uncertainty about the drug's overall risk-benefit profile.
Small Benefit, Big Risk
The current study is the first comprehensive systematic review to evaluate tramadol alone for chronic pain using both meta-analysis and trail sequential analysis, provided a broader view of efficacy and safety across pain types.
"We sought to fill this gap by evaluating the totality of evidence to guide clinical practice," Barakji said.
The analysis included 19 randomized, placebo-controlled trials with 6569 adults. The average participant age was 56 years, and study durations ranged from 4 to 16 weeks. Pain intensity was typically assessed with the 0-10 numeric rating scale (NRS), while function and quality of life were measured with validated patient-reported tools.
Across the pooled analysis, participants receiving tramadol experienced an average pain reduction of 0.9 points on the NRS compared with placebo - a difference below the 1-point threshold considered clinically meaningful. About 7% more patients in the tramadol groups achieved noticeable pain relief, but investigators said the benefit was modest and uncertain.
Serious adverse events were twice as common among tramadol users, most often involving cardiac complications such as chest pain, coronary artery disease, or heart failure. Nonserious adverse effects, including nausea, dizziness, constipation, and drowsiness, were frequent and contributed to higher discontinuation rates among tramadol recipients.
The researchers acknowledged that most included trials were at a high risk for bias due to incomplete outcome reporting, small sample sizes, and inconsistent assessment methods, factors that may have exaggerated benefits and underestimated harms.
Reevaluating Tramadol's Role
Commenting on the research, Jessica Otte, MD, clinical associate professor in the Department of Family Medicine at The University of British Columbia, Vancouver, British Columbia, Canada, said the new review stands out for examining tramadol's use across a range of chronic pain conditions, an area where clinicians often struggle to help patients achieve meaningful and sustained relief.
Otte, who has studied the drug's safety and effectiveness through The University of British Columbia's Therapeutics Initiative, said the Danish team's analysis expands on earlier research that largely focused on single pain conditions. The findings, she said, add weight to growing evidence that challenges tramadol's perceived advantages over other analgesics.
"This review doesn't change the narrative but strengthens it: Tramdol's reputation as a safer or uniquely effective opioid is increasingly difficult to defend," she told Medscape Medical News.
While she believes the study makes an important contribution, Otte said the results should be interpreted with caution because of gaps in the underlying evidence. The Danish authors noted similar concerns, and Otte agreed that many of the included trials had methodological shortcomings.
"A lot of the studies had biases that made use less certain about what was reported," she said. "Many outcomes that matter to patients - like quality of life, functional improvement, or withdrawal - were either inconsistently measured or not reported at all."
She added that patients assigned to tramadol were more likely to discontinue early, both overall and because of adverse effects, raising concern about tolerability and attrition bias.
Also commenting, Houman Danesh, MD, professor and medical director of pain management at the Icahn School of Medicine at Mount Sinai in New York City, said the review provides moderate-certainty evidence that tramadol increases the risk for serious adverse events; but its broad approach - evaluating efficacy and safety across multiple chronic pain conditions - could be a confounding factor.
"Tramadol may benefit some conditions more than others," he noted, which could alter the overall risk-benefit profile.
In his clinical experience, Danesh said severe complications such as cardiac events are uncommon. He explained that heart rhythm disturbances occasionally associated with tramadol generally arise when patients are taking other medications that affect cardiac conduction.
Danesh emphasized that clinicians should weigh the study alongside other research and their own experience when deciding whether to prescribe the drug.
"It's important to take this study into consideration," he said, "but there are multiple studies that support the use of tramadol, and we have to look at the totality of the evidence."
Written by Carla Cantor.
The authors declared no competing interests and received no specific grant from any funding agency. Otte and Danesh reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Tramadol, a commonly prescribed opioid often viewed as a safer option for chronic pain, provided limited pain relief while increasing the risk for serious adverse effects, results of a new analysis showed.
In a systematic review and meta-analysis, investigators found that tramadol offered clinically insignificant pain relief, while doubling the likelihood of serious adverse events, most commonly cardiac complications.
"Given the limited analgesic benefits and increased risk of harm, tramadol use for chronic pain should be reconsidered," Jehad Ahmad Barakji, MD, of the Centre for Clinical Intervention Research at Rigshospitalet in Copenhagen, Denmark, told Medscape Medical News.
"Across different chronic pain conditions, tramadol's pain-relieving effect appears modest, and while some patients may experience relief, most will not gain substantial benefit," he added.
However, the researchers cautioned that the certainty of the evidence was low-to-moderate and that the quality of the underlying trials varied substantially.
The study was published on October 7 in BMJ Evidence-Based Medicine.
Popularity Outpacing Proof
Tramadol, a dual-action opioid that modulates serotonin and norepinephrine pathways, has long been promoted as a middle-ground analgesic - less addictive than morphine but stronger than nonopioid medications. It is approved for moderate-to-severe pain, including postoperative and chronic conditions.
Prescriptions have risen sharply worldwide, fueled by perceptions of safety and a belief that tramadol carries a lower risk for dependence. A recent global analysis estimated that nearly 18% of adults have used tramadol in their lifetime, and > 80% of those users combined it with at least 1 other substance.
Despite its widespread use, evidence supporting tramadol's long-term effectiveness and safety in chronic pain has been limited and inconsistent. Previous research has largely focused on short-term or condition-specific outcomes, such as osteoarthritis or neuropathic pain, leaving uncertainty about the drug's overall risk-benefit profile.
Small Benefit, Big Risk
The current study is the first comprehensive systematic review to evaluate tramadol alone for chronic pain using both meta-analysis and trail sequential analysis, provided a broader view of efficacy and safety across pain types.
"We sought to fill this gap by evaluating the totality of evidence to guide clinical practice," Barakji said.
The analysis included 19 randomized, placebo-controlled trials with 6569 adults. The average participant age was 56 years, and study durations ranged from 4 to 16 weeks. Pain intensity was typically assessed with the 0-10 numeric rating scale (NRS), while function and quality of life were measured with validated patient-reported tools.
Across the pooled analysis, participants receiving tramadol experienced an average pain reduction of 0.9 points on the NRS compared with placebo - a difference below the 1-point threshold considered clinically meaningful. About 7% more patients in the tramadol groups achieved noticeable pain relief, but investigators said the benefit was modest and uncertain.
Serious adverse events were twice as common among tramadol users, most often involving cardiac complications such as chest pain, coronary artery disease, or heart failure. Nonserious adverse effects, including nausea, dizziness, constipation, and drowsiness, were frequent and contributed to higher discontinuation rates among tramadol recipients.
The researchers acknowledged that most included trials were at a high risk for bias due to incomplete outcome reporting, small sample sizes, and inconsistent assessment methods, factors that may have exaggerated benefits and underestimated harms.
Reevaluating Tramadol's Role
Commenting on the research, Jessica Otte, MD, clinical associate professor in the Department of Family Medicine at The University of British Columbia, Vancouver, British Columbia, Canada, said the new review stands out for examining tramadol's use across a range of chronic pain conditions, an area where clinicians often struggle to help patients achieve meaningful and sustained relief.
Otte, who has studied the drug's safety and effectiveness through The University of British Columbia's Therapeutics Initiative, said the Danish team's analysis expands on earlier research that largely focused on single pain conditions. The findings, she said, add weight to growing evidence that challenges tramadol's perceived advantages over other analgesics.
"This review doesn't change the narrative but strengthens it: Tramdol's reputation as a safer or uniquely effective opioid is increasingly difficult to defend," she told Medscape Medical News.
While she believes the study makes an important contribution, Otte said the results should be interpreted with caution because of gaps in the underlying evidence. The Danish authors noted similar concerns, and Otte agreed that many of the included trials had methodological shortcomings.
"A lot of the studies had biases that made use less certain about what was reported," she said. "Many outcomes that matter to patients - like quality of life, functional improvement, or withdrawal - were either inconsistently measured or not reported at all."
She added that patients assigned to tramadol were more likely to discontinue early, both overall and because of adverse effects, raising concern about tolerability and attrition bias.
Also commenting, Houman Danesh, MD, professor and medical director of pain management at the Icahn School of Medicine at Mount Sinai in New York City, said the review provides moderate-certainty evidence that tramadol increases the risk for serious adverse events; but its broad approach - evaluating efficacy and safety across multiple chronic pain conditions - could be a confounding factor.
"Tramadol may benefit some conditions more than others," he noted, which could alter the overall risk-benefit profile.
In his clinical experience, Danesh said severe complications such as cardiac events are uncommon. He explained that heart rhythm disturbances occasionally associated with tramadol generally arise when patients are taking other medications that affect cardiac conduction.
Danesh emphasized that clinicians should weigh the study alongside other research and their own experience when deciding whether to prescribe the drug.
"It's important to take this study into consideration," he said, "but there are multiple studies that support the use of tramadol, and we have to look at the totality of the evidence."
Written by Carla Cantor.
The authors declared no competing interests and received no specific grant from any funding agency. Otte and Danesh reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Time to Reconsider Tramadol for Chronic Pain?
Time to Reconsider Tramadol for Chronic Pain?
Is low-dose naltrexone effective in chronic pain management?
Evidence summary
Naltrexone is comparable to amitriptyline for diabetic neuropathy pain
A 2021 randomized, double-blind, active-comparator, crossover clinical trial conducted in India examined the efficacy of low-dose naltrexone vs standard-of-care amitriptyline in patients (N = 67) with painful diabetic neuropathy. Participants were adults (ages 18 to 75 years) with painful diabetic neuropathy who had been on a stable dose of nonopioid pain medication for at least 1 month.1
Patients were randomly assigned to start receiving naltrexone 2 mg (n = 33) or amitriptyline 10 mg (n = 34). They received their starting medication for 6 weeks (with follow-up every 2 weeks), then completed a 2-week washout period, and then switched to the other study medication for 6 weeks (same follow-up schedule). If patients reported < 20% pain reduction on the Visual Analog Scale (VAS; 0-100 scoring system with 0 = no pain and 100 = worst pain) at a follow-up visit, their medication dose was titrated up, to a maximum of 4 mg of naltrexone or 25 to 50 mg of amitriptyline.1
The primary outcome of interest was the mean change in VAS pain score following 6 weeks of treatment. There was no statistically different change from baseline VAS pain score between the amitriptyline and naltrexone groups (mean difference [MD] = 1.6; 95% CI, –0.9 to 4.2; P = 0.21). These findings were consistent across the secondary endpoints (Likert 5-point pain scale and McGill Pain Questionnaire scores). There was no statistically significant difference in Hamilton Depression Rating Scale scores (13 in the naltrexone group vs 11 in the amitriptyline group; P = .81), no reports of decreased sleep quality in either group, and no significant difference in Patients’ Global Impression of Change scores at 6-week evaluation.1
The naltrexone cohort experienced 8 adverse events (most commonly, mild diarrhea), while the amitriptyline cohort experienced 52 adverse events (most commonly, somnolence) (P < .001). The limitations of the study include the lack of a placebo arm and a relatively small sample size.1
Greater reduction in pain scores with naltrexone
A 2022 retrospective cohort study evaluated the effectiveness of naltrexone for patients treated at a single outpatient integrative pain management practice in Alaska between 2014 and 2019. The exposure group (n = 36) included patients who had completed at least a 2-month continuous regimen of oral naltrexone 4.5 mg. Controls (n = 42) were selected from the remaining practice population receiving standard care and were primarily matched by diagnosis code, followed by gender, then age +/– 5 years. Patients were divided into subgroups for inflammatory and neuropathic pain.2
The primary outcome measured was the mean change in VAS score or numeric rating score (NRS; both used a 1-10 rating system), which was assessed during a patient’s appointment from initiation of treatment to the most recent visit or at the termination of therapy (intervention interquartile range, 12-14 months). There was no statistically significant difference in VAS/NRS between the low-dose naltrexone and control groups at baseline (6.09 vs 6.38; P = .454). The low-dose naltrexone group experienced a greater reduction in VAS/NRS pain scores compared to the control group (–37.8% vs –4.3%; P < .001).2
Compared with control patients in each group, patients in the inflammatory pain subgroup and the neuropathic pain subgroup who received low-dose naltrexone reported reductions in pain scores of 32% (P < .001) and 44% (P = .048), respectively. There was no statistically significant difference in mean change in VAS/NRS scores between the inflammatory and neuropathic subgroups (P = .763). A multivariate linear regression analysis did not identify significant variables other than low-dose naltrexone that correlated with pain improvement. The number needed to treat to observe a ≥ 50% reduction in pain scores was 3.2.2
Continue to: Limitations for this study...
Limitations for this study include its small sample size and open-label design.2
Low-dose naltrexone is effective for fibromyalgia pain
A 2020 single-blind prospective dose-response study utilized the up-and-down method to identify effective naltrexone dose for patients in a Danish university hospital pain clinic. Patients were White women ages 18 to 60 years (N = 25) who had a diagnosis of fibromyalgia unresponsive to traditional pharmacologic treatment. All patients received treatment with low-dose naltrexone (ranging from 0.75 mg to 6.0 mg) but were blinded to dose.3
Patients were evaluated for improvement in fibromyalgia symptoms using the Patient Global Impression of Improvement (PGI-I) scale—which ranges from 1 (very much improved) to 7 (very much worse), with 4 being “no change”—at baseline and after 2 to 3 weeks of treatment with low-dose naltrexone. A patient was considered a responder if they scored 1 to 3 on the follow-up PGI-I scale or if they experienced a > 30% pain reduction on the VAS. If a patient did not respond to their dose, the next patient began treatment at a dose 0.75 mg higher than the previous patient’s ending dose. If a patient did respond to low-dose naltrexone treatment, the next patient’s starting dose was 0.75 mg less than the previous patient’s. Eleven of 25 patients were considered responders.3
The primary outcomes were effective dose for 50% of fibromyalgia patients (3.88 mg; 95% CI, 3.39-4.35) and effective dose for 95% of fibromyalgia patients (5.4 mg; 95% CI, 4.66-6.13). Secondary outcomes were fibromyalgia symptoms as evaluated on the Fibromyalgia Impact Questionnaire Revised. Five of the 11 responders reported a > 30% improvement in tenderness and 8 of the 11 responders reported a > 30% decrease in waking unrefreshed.3
Limitations of the study include the short time period of treatment before response was assessed and the decision to use low test doses, which may have hindered detection of effective doses > 6 mg in fibromyalgia.3
Editor’s takeaway
Low-dose naltrexone, a less-often-used form of pain management, is a welcome option. Studies show some effectiveness in a variety of pain conditions with few adverse effects. The small number of studies, the small sample sizes, and the limited follow-up duration should encourage more investigation into how to best use this intervention.
1. Srinivasan A, Dutta P, Bansal D, et al. Efficacy and safety of low-dose naltrexone in painful diabetic neuropathy: a randomized, double-blind, active-control, crossover clinical trial. J Diabetes. 2021;13:770-778. doi: 10.1111/1753-0407.13202
2. Martin SJ, McAnally HB, Okediji P, et al. Low-dose naltrexone, an opioid-receptor antagonist, is a broad-spectrum analgesic: a retrospective cohort study. Pain Management. 2022;12:699-709. doi: 10.2217/pmt-2021-0122
3. Bruun-Plesner K, Blichfeldt-Eckhardt MR, Vaegter HB, et al. Low-dose naltrexone for the treatment of fibromyalgia: investigation of dose-response relationships. Pain Med. 2020;21:2253-2261. doi: 10.1093/pm/pnaa001
Evidence summary
Naltrexone is comparable to amitriptyline for diabetic neuropathy pain
A 2021 randomized, double-blind, active-comparator, crossover clinical trial conducted in India examined the efficacy of low-dose naltrexone vs standard-of-care amitriptyline in patients (N = 67) with painful diabetic neuropathy. Participants were adults (ages 18 to 75 years) with painful diabetic neuropathy who had been on a stable dose of nonopioid pain medication for at least 1 month.1
Patients were randomly assigned to start receiving naltrexone 2 mg (n = 33) or amitriptyline 10 mg (n = 34). They received their starting medication for 6 weeks (with follow-up every 2 weeks), then completed a 2-week washout period, and then switched to the other study medication for 6 weeks (same follow-up schedule). If patients reported < 20% pain reduction on the Visual Analog Scale (VAS; 0-100 scoring system with 0 = no pain and 100 = worst pain) at a follow-up visit, their medication dose was titrated up, to a maximum of 4 mg of naltrexone or 25 to 50 mg of amitriptyline.1
The primary outcome of interest was the mean change in VAS pain score following 6 weeks of treatment. There was no statistically different change from baseline VAS pain score between the amitriptyline and naltrexone groups (mean difference [MD] = 1.6; 95% CI, –0.9 to 4.2; P = 0.21). These findings were consistent across the secondary endpoints (Likert 5-point pain scale and McGill Pain Questionnaire scores). There was no statistically significant difference in Hamilton Depression Rating Scale scores (13 in the naltrexone group vs 11 in the amitriptyline group; P = .81), no reports of decreased sleep quality in either group, and no significant difference in Patients’ Global Impression of Change scores at 6-week evaluation.1
The naltrexone cohort experienced 8 adverse events (most commonly, mild diarrhea), while the amitriptyline cohort experienced 52 adverse events (most commonly, somnolence) (P < .001). The limitations of the study include the lack of a placebo arm and a relatively small sample size.1
Greater reduction in pain scores with naltrexone
A 2022 retrospective cohort study evaluated the effectiveness of naltrexone for patients treated at a single outpatient integrative pain management practice in Alaska between 2014 and 2019. The exposure group (n = 36) included patients who had completed at least a 2-month continuous regimen of oral naltrexone 4.5 mg. Controls (n = 42) were selected from the remaining practice population receiving standard care and were primarily matched by diagnosis code, followed by gender, then age +/– 5 years. Patients were divided into subgroups for inflammatory and neuropathic pain.2
The primary outcome measured was the mean change in VAS score or numeric rating score (NRS; both used a 1-10 rating system), which was assessed during a patient’s appointment from initiation of treatment to the most recent visit or at the termination of therapy (intervention interquartile range, 12-14 months). There was no statistically significant difference in VAS/NRS between the low-dose naltrexone and control groups at baseline (6.09 vs 6.38; P = .454). The low-dose naltrexone group experienced a greater reduction in VAS/NRS pain scores compared to the control group (–37.8% vs –4.3%; P < .001).2
Compared with control patients in each group, patients in the inflammatory pain subgroup and the neuropathic pain subgroup who received low-dose naltrexone reported reductions in pain scores of 32% (P < .001) and 44% (P = .048), respectively. There was no statistically significant difference in mean change in VAS/NRS scores between the inflammatory and neuropathic subgroups (P = .763). A multivariate linear regression analysis did not identify significant variables other than low-dose naltrexone that correlated with pain improvement. The number needed to treat to observe a ≥ 50% reduction in pain scores was 3.2.2
Continue to: Limitations for this study...
Limitations for this study include its small sample size and open-label design.2
Low-dose naltrexone is effective for fibromyalgia pain
A 2020 single-blind prospective dose-response study utilized the up-and-down method to identify effective naltrexone dose for patients in a Danish university hospital pain clinic. Patients were White women ages 18 to 60 years (N = 25) who had a diagnosis of fibromyalgia unresponsive to traditional pharmacologic treatment. All patients received treatment with low-dose naltrexone (ranging from 0.75 mg to 6.0 mg) but were blinded to dose.3
Patients were evaluated for improvement in fibromyalgia symptoms using the Patient Global Impression of Improvement (PGI-I) scale—which ranges from 1 (very much improved) to 7 (very much worse), with 4 being “no change”—at baseline and after 2 to 3 weeks of treatment with low-dose naltrexone. A patient was considered a responder if they scored 1 to 3 on the follow-up PGI-I scale or if they experienced a > 30% pain reduction on the VAS. If a patient did not respond to their dose, the next patient began treatment at a dose 0.75 mg higher than the previous patient’s ending dose. If a patient did respond to low-dose naltrexone treatment, the next patient’s starting dose was 0.75 mg less than the previous patient’s. Eleven of 25 patients were considered responders.3
The primary outcomes were effective dose for 50% of fibromyalgia patients (3.88 mg; 95% CI, 3.39-4.35) and effective dose for 95% of fibromyalgia patients (5.4 mg; 95% CI, 4.66-6.13). Secondary outcomes were fibromyalgia symptoms as evaluated on the Fibromyalgia Impact Questionnaire Revised. Five of the 11 responders reported a > 30% improvement in tenderness and 8 of the 11 responders reported a > 30% decrease in waking unrefreshed.3
Limitations of the study include the short time period of treatment before response was assessed and the decision to use low test doses, which may have hindered detection of effective doses > 6 mg in fibromyalgia.3
Editor’s takeaway
Low-dose naltrexone, a less-often-used form of pain management, is a welcome option. Studies show some effectiveness in a variety of pain conditions with few adverse effects. The small number of studies, the small sample sizes, and the limited follow-up duration should encourage more investigation into how to best use this intervention.
Evidence summary
Naltrexone is comparable to amitriptyline for diabetic neuropathy pain
A 2021 randomized, double-blind, active-comparator, crossover clinical trial conducted in India examined the efficacy of low-dose naltrexone vs standard-of-care amitriptyline in patients (N = 67) with painful diabetic neuropathy. Participants were adults (ages 18 to 75 years) with painful diabetic neuropathy who had been on a stable dose of nonopioid pain medication for at least 1 month.1
Patients were randomly assigned to start receiving naltrexone 2 mg (n = 33) or amitriptyline 10 mg (n = 34). They received their starting medication for 6 weeks (with follow-up every 2 weeks), then completed a 2-week washout period, and then switched to the other study medication for 6 weeks (same follow-up schedule). If patients reported < 20% pain reduction on the Visual Analog Scale (VAS; 0-100 scoring system with 0 = no pain and 100 = worst pain) at a follow-up visit, their medication dose was titrated up, to a maximum of 4 mg of naltrexone or 25 to 50 mg of amitriptyline.1
The primary outcome of interest was the mean change in VAS pain score following 6 weeks of treatment. There was no statistically different change from baseline VAS pain score between the amitriptyline and naltrexone groups (mean difference [MD] = 1.6; 95% CI, –0.9 to 4.2; P = 0.21). These findings were consistent across the secondary endpoints (Likert 5-point pain scale and McGill Pain Questionnaire scores). There was no statistically significant difference in Hamilton Depression Rating Scale scores (13 in the naltrexone group vs 11 in the amitriptyline group; P = .81), no reports of decreased sleep quality in either group, and no significant difference in Patients’ Global Impression of Change scores at 6-week evaluation.1
The naltrexone cohort experienced 8 adverse events (most commonly, mild diarrhea), while the amitriptyline cohort experienced 52 adverse events (most commonly, somnolence) (P < .001). The limitations of the study include the lack of a placebo arm and a relatively small sample size.1
Greater reduction in pain scores with naltrexone
A 2022 retrospective cohort study evaluated the effectiveness of naltrexone for patients treated at a single outpatient integrative pain management practice in Alaska between 2014 and 2019. The exposure group (n = 36) included patients who had completed at least a 2-month continuous regimen of oral naltrexone 4.5 mg. Controls (n = 42) were selected from the remaining practice population receiving standard care and were primarily matched by diagnosis code, followed by gender, then age +/– 5 years. Patients were divided into subgroups for inflammatory and neuropathic pain.2
The primary outcome measured was the mean change in VAS score or numeric rating score (NRS; both used a 1-10 rating system), which was assessed during a patient’s appointment from initiation of treatment to the most recent visit or at the termination of therapy (intervention interquartile range, 12-14 months). There was no statistically significant difference in VAS/NRS between the low-dose naltrexone and control groups at baseline (6.09 vs 6.38; P = .454). The low-dose naltrexone group experienced a greater reduction in VAS/NRS pain scores compared to the control group (–37.8% vs –4.3%; P < .001).2
Compared with control patients in each group, patients in the inflammatory pain subgroup and the neuropathic pain subgroup who received low-dose naltrexone reported reductions in pain scores of 32% (P < .001) and 44% (P = .048), respectively. There was no statistically significant difference in mean change in VAS/NRS scores between the inflammatory and neuropathic subgroups (P = .763). A multivariate linear regression analysis did not identify significant variables other than low-dose naltrexone that correlated with pain improvement. The number needed to treat to observe a ≥ 50% reduction in pain scores was 3.2.2
Continue to: Limitations for this study...
Limitations for this study include its small sample size and open-label design.2
Low-dose naltrexone is effective for fibromyalgia pain
A 2020 single-blind prospective dose-response study utilized the up-and-down method to identify effective naltrexone dose for patients in a Danish university hospital pain clinic. Patients were White women ages 18 to 60 years (N = 25) who had a diagnosis of fibromyalgia unresponsive to traditional pharmacologic treatment. All patients received treatment with low-dose naltrexone (ranging from 0.75 mg to 6.0 mg) but were blinded to dose.3
Patients were evaluated for improvement in fibromyalgia symptoms using the Patient Global Impression of Improvement (PGI-I) scale—which ranges from 1 (very much improved) to 7 (very much worse), with 4 being “no change”—at baseline and after 2 to 3 weeks of treatment with low-dose naltrexone. A patient was considered a responder if they scored 1 to 3 on the follow-up PGI-I scale or if they experienced a > 30% pain reduction on the VAS. If a patient did not respond to their dose, the next patient began treatment at a dose 0.75 mg higher than the previous patient’s ending dose. If a patient did respond to low-dose naltrexone treatment, the next patient’s starting dose was 0.75 mg less than the previous patient’s. Eleven of 25 patients were considered responders.3
The primary outcomes were effective dose for 50% of fibromyalgia patients (3.88 mg; 95% CI, 3.39-4.35) and effective dose for 95% of fibromyalgia patients (5.4 mg; 95% CI, 4.66-6.13). Secondary outcomes were fibromyalgia symptoms as evaluated on the Fibromyalgia Impact Questionnaire Revised. Five of the 11 responders reported a > 30% improvement in tenderness and 8 of the 11 responders reported a > 30% decrease in waking unrefreshed.3
Limitations of the study include the short time period of treatment before response was assessed and the decision to use low test doses, which may have hindered detection of effective doses > 6 mg in fibromyalgia.3
Editor’s takeaway
Low-dose naltrexone, a less-often-used form of pain management, is a welcome option. Studies show some effectiveness in a variety of pain conditions with few adverse effects. The small number of studies, the small sample sizes, and the limited follow-up duration should encourage more investigation into how to best use this intervention.
1. Srinivasan A, Dutta P, Bansal D, et al. Efficacy and safety of low-dose naltrexone in painful diabetic neuropathy: a randomized, double-blind, active-control, crossover clinical trial. J Diabetes. 2021;13:770-778. doi: 10.1111/1753-0407.13202
2. Martin SJ, McAnally HB, Okediji P, et al. Low-dose naltrexone, an opioid-receptor antagonist, is a broad-spectrum analgesic: a retrospective cohort study. Pain Management. 2022;12:699-709. doi: 10.2217/pmt-2021-0122
3. Bruun-Plesner K, Blichfeldt-Eckhardt MR, Vaegter HB, et al. Low-dose naltrexone for the treatment of fibromyalgia: investigation of dose-response relationships. Pain Med. 2020;21:2253-2261. doi: 10.1093/pm/pnaa001
1. Srinivasan A, Dutta P, Bansal D, et al. Efficacy and safety of low-dose naltrexone in painful diabetic neuropathy: a randomized, double-blind, active-control, crossover clinical trial. J Diabetes. 2021;13:770-778. doi: 10.1111/1753-0407.13202
2. Martin SJ, McAnally HB, Okediji P, et al. Low-dose naltrexone, an opioid-receptor antagonist, is a broad-spectrum analgesic: a retrospective cohort study. Pain Management. 2022;12:699-709. doi: 10.2217/pmt-2021-0122
3. Bruun-Plesner K, Blichfeldt-Eckhardt MR, Vaegter HB, et al. Low-dose naltrexone for the treatment of fibromyalgia: investigation of dose-response relationships. Pain Med. 2020;21:2253-2261. doi: 10.1093/pm/pnaa001
EVIDENCE-BASED ANSWER:
YES. Low-dose naltrexone is as effective as amitriptyline in the treatment of painful diabetic neuropathy and has a superior safety profile (strength of recommendation [SOR], B; single randomized controlled trial [RCT]).
Low-dose naltrexone significantly reduced pain by 32% in inflammatory conditions and 44% in neuropathic conditions (SOR, B; single retrospective cohort study).
Doses as low as 5.4 mg were found to reduce pain in 95% of patients with fibromyalgia (SOR, B; single prospective dose-response study).
