Combination Therapy for Neuropathic Pain — Which Drugs, Which Combination, Which Patients?
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《新英格兰医药杂志》
Neuropathic pain is a complex, costly condition resulting from a primary lesion or dysfunction in any part of the nervous system, from the peripheral receptor to the brain. Degenerative spine disease, diabetes, herpes zoster, compression and entrapment syndromes, AIDS, surgeries such as thoracotomies and mastectomies, amputation, spinal cord injury, and stroke are common causes of neuropathic pain. The aging of the population and the rising prevalence of many of these conditions forecast a probable increase in the number of patients who will have neuropathic pain. Persistent neuropathic pain usually alters a patient's quality of life by interfering with sleep, work, recreation, and emotional well-being.
Although the causes of neuropathic pain are diverse, patients typically present with varying combinations of positive and negative signs and symptoms. Positive symptoms can result from changes in the peripheral nerves, such as ectopic activity due to injured sensory neurons and increased excitability of adjacent uninjured neurons (peripheral sensitization). A loss of inhibitory mechanisms in the central nervous system and an increase in the sensitivity of neurons in the spinal cord and higher centers (central sensitization) may also result in positive symptoms. Ongoing pain, nonpainful or unpleasant paresthesias, pain evoked by light brushing of the skin (allodynia), and exaggerated or prolonged pain from pinprick (hyperalgesia or hyperpathia) are positive features. These symptoms may spread beyond the innervation territory of the affected nerve. Negative symptoms reflect axonal or neuronal loss and include sensory deficits in response to touch, temperature, or pinprick.
Recent advances in pain research indicate multiple mechanisms underlying the initiation and maintenance of neuropathic pain.1 Ideally, elucidating the mechanisms for pain in a patient could lead to targeted, mechanism-based therapy.2 However, the similarity of symptoms among patients does not imply common mechanisms, even when the cause of the pain is the same.3 For some patients, the pathophysiology of the mechanisms may primarily affect the peripheral nervous system, whereas for others the predominant mechanisms may affect the central nervous system.
The available therapies shown to be effective in managing neuropathic pain include anticonvulsant drugs, tricyclic antidepressant drugs, opioids, topical lidocaine, new antidepressant drugs such as duloxetine and venlafaxine, and the analgesic agent tramadol.4,5 The anticonvulsant drug gabapentin is used frequently to control pain in postherpetic neuralgia and diabetic neuropathy, on the basis of evidence of efficacy from randomized trials.6,7 The mechanism of action in gabapentin is unclear, but its effects on the 2 calcium-channel subunit may result in the decreased release of neurotransmitters and the suppression of central sensitization.
Opioids are also recommended as first-line treatment for neuropathic pain.5 Although their use was initially controversial, the benefits of opioids for neuropathic pain have been shown in studies of infused opioids, in a series of trials of oral medication, and even in comparison with alternative therapies.8 In a crossover study comparing opioids and tricyclic antidepressant drugs in patients with postherpetic neuralgia, we observed similar reductions in pain intensity with the use of opioids and antidepressants, but patients reported greater satisfaction with opioid therapy.9 Like the majority of opioid trials, our study used long-acting formulations and around-the-clock doses. The use of short-acting opioids is generally recommended only during an initial titration period or as an adjunct to the use of long-acting formulations to relieve breakthrough pain.
In the clinical management of neuropathic pain, when pain relief with gabapentin is incomplete, expert panels recommend adding a second analgesic agent, which may be an opioid. Until now, recommendations for combination therapy were based on theoretical mechanisms, rather than on controlled trials. In this issue of the Journal, Gilron et al.10 provide evidence of the efficacy of a combination of gabapentin and morphine in reducing pain and pain-related disability in patients with either diabetic neuropathy or postherpetic neuralgia. This double-blind, randomized, crossover trial compared monotherapy and combination therapy with active placebo (lorazepam). As in clinical practice, the study drugs were titrated with the objective of balancing analgesia and adverse effects. The combination treatment with morphine and gabapentin resulted in a greater reduction in pain than did gabapentin alone, morphine alone, or placebo. The combination therapy also had beneficial effects on pain-related interference with daily activities, mood, and health-related quality of life. The combination therapy resulted in a greater frequency of constipation than gabapentin alone did and a greater frequency of dry mouth than morphine alone did. The use of an active comparator drug is a particular strength of the trial design, and few patients (25 percent) correctly identified when they were receiving the gabapentin–morphine combination.
The titration procedure allowed the study nurse and the patients to find the best balance between analgesia and adverse effects. It probably contributed to the relatively low rate of adverse effects and enhances the generalizability of these findings to clinical care. With concurrent titration, patients stopped increasing the levels of gabapentin and morphine at lower doses of each agent when the two drugs were given in combination than they did when receiving each as monotherapy. As a result, treatment with the combination of gabapentin and morphine yielded greater reductions in pain and improvements in daily functioning with lower doses of each medication than each did alone.
Practical issues arise in applying these findings in clinical practice. For example, is combination therapy best given sequentially, as is typically recommended, or concurrently, as in the trial by Gilron et al.? Sequential therapy offers the opportunity to identify patients who do not respond to a single agent before the addition of a second agent. This may be especially valuable in treating patients with coexisting conditions that require multiple other medications or when drug interactions should be taken into account. However, the benefits of concurrent combination therapy shown in this study, including lower doses with greater pain relief and tolerable adverse effects, might be due to the simultaneous titration of the two drugs. The difference between recommended practice and the method of Gilron et al. deserves critical scrutiny in the future to determine whether sequential titration and concurrent titration of combination therapies yield different outcomes.
Since clinical trials often select patients who adhere maximally to study procedures and offer them considerable support during drug titration, actual adherence to combination therapy may be substantially lower in routine clinical settings. Unfortunately, little is known about adherence in the use of pain medications generally, but improved adherence to therapy with opioids does occur with a regular schedule of doses rather than with doses given as needed.11 Although a combined formulation was not used in this trial, such formulations may improve adherence, as has been shown with antiretroviral therapy.
Trials such as that conducted by Gilron and colleagues need to address additional challenges facing clinicians who are struggling to reduce neuropathic pain in the individual patient. For example, patients were satisfied with their pain relief and stopped increasing drug doses at an average pain level of 3 (on a scale from 0 to 10). How much pain, if any, is acceptable to patients who have chronic neuropathic pain? In deciding which treatment and which combination to use, does the response to a single agent predict the response to the combination? In deciding which treatment is appropriate to which patient, can preexisting patient characteristics, such as sex, genetic profile, and mechanisms underlying the persistent pain, predict the response to one agent as opposed to another? In deciding on combination therapy, do additive or synergistic effects occur with some combinations and not with others?
The study by Gilron et al. was not designed to test whether combination therapy is synergistic, or even additive. Preclinical studies, however, suggest a potential synergy between gabapentin and opioids.12 It is important to ascertain whether the lower drug doses obtained with the use of the combination therapy extend to reduced tolerance or the potential for abuse. Close examination of the data in the present study10 suggests that prior exposure to morphine may have reduced the beneficial effects of gabapentin. Identifying such subtleties in treatment response will require large-scale investigation.
As with various chronic conditions, the management of neuropathic pain remains challenging in many patients. This study clearly shows the advantages of concurrent titration of gabapentin and morphine, though the perceived risks of addiction and diversion with opioids and the fear of scrutiny by regulatory agencies may present barriers to the acceptance of this combination as first-line treatment. In addition to developing and testing new pharmacologic agents, we need clinical trials that will examine which drugs in which combination, used for which patients, provide effective pain relief with the lowest doses and tolerable adverse effects.
Supported in part by grants (NIH-NS26363, to Dr. Raja, and NIH-NS02225, to Dr. Haythornthwaite) from the National Institutes of Health.
Dr. Raja reports having received compensation from an unrestricted educational grant awarded by Pfizer to the Johns Hopkins University School of Medicine to develop a continuing medical education teaching module. Dr. Haythornthwaite reports having received a fee from Pfizer to review competitive grant applications for young investigators.
Source Information
From the Departments of Anesthesiology and Critical Care Medicine (S.N.R.) and Psychiatry and Behavioral Science (J.A.H.), Johns Hopkins University School of Medicine, Baltimore.
References
Woolf CJ. Dissecting out mechanisms responsible for peripheral neuropathic pain: implications for diagnosis and therapy. Life Sci 2004;74:2605-2610.
Woolf CJ, Decosterd I. Implications of recent advances in the understanding of pain pathophysiology for the assessment of pain in patients. Pain 1999;82:Suppl 1:S141-S147.
Fields HL, Rowbotham M, Baron R. Postherpetic neuralgia: irritable nociceptors and deafferentation. Neurobiol Dis 1998;5:209-227.
Chen H, Lamer TJ, Rho RH, et al. Contemporary management of neuropathic pain for the primary care physician. Mayo Clin Proc 2004;79:1533-1545.
Dworkin RH, Backonja M, Rowbotham MC, et al. Advances in neuropathic pain: diagnosis, mechanisms, and treatment recommendations. Arch Neurol 2003;60:1524-1534.
Rowbotham M, Harden N, Stacey B, Bernstein P, Magnus-Miller L. Gabapentin for the treatment of postherpetic neuralgia: a randomized controlled trial. JAMA 1998;280:1837-1842.
Backonja M, Beydoun A, Edwards KR, et al. Gabapentin for the symptomatic treatment of painful neuropathy in patients with diabetes mellitus: a randomized controlled trial. JAMA 1998;280:1831-1836.
Ballantyne JC, Mao J. Opioid therapy for chronic pain. N Engl J Med 2003;349:1943-1953.
Raja SN, Haythornthwaite JA, Pappagallo M, et al. Opioids versus antidepressants in postherpetic neuralgia: a randomized, placebo-controlled trial. Neurology 2002;59:1015-1021.
Gilron I, Bailey JM, Tu D, Holden RR, Weaver DF, Houlden RL. Morphine, gabapentin, or their combination for neuropathic pain. N Engl J Med 2005;352:1324-1334.
Miaskowski C, Dodd MJ, West C, et al. Lack of adherence with the analgesic regimen: a significant barrier to effective cancer pain management. J Clin Oncol 2001;19:4275-4279.
Eckhardt K, Ammon S, Hofmann U, Riebe A, Gugeler N, Mikus G. Gabapentin enhances the analgesic effect of morphine in healthy volunteers. Anesth Analg 2000;91:185-191.(Srinivasa N. Raja, M.D., )
Although the causes of neuropathic pain are diverse, patients typically present with varying combinations of positive and negative signs and symptoms. Positive symptoms can result from changes in the peripheral nerves, such as ectopic activity due to injured sensory neurons and increased excitability of adjacent uninjured neurons (peripheral sensitization). A loss of inhibitory mechanisms in the central nervous system and an increase in the sensitivity of neurons in the spinal cord and higher centers (central sensitization) may also result in positive symptoms. Ongoing pain, nonpainful or unpleasant paresthesias, pain evoked by light brushing of the skin (allodynia), and exaggerated or prolonged pain from pinprick (hyperalgesia or hyperpathia) are positive features. These symptoms may spread beyond the innervation territory of the affected nerve. Negative symptoms reflect axonal or neuronal loss and include sensory deficits in response to touch, temperature, or pinprick.
Recent advances in pain research indicate multiple mechanisms underlying the initiation and maintenance of neuropathic pain.1 Ideally, elucidating the mechanisms for pain in a patient could lead to targeted, mechanism-based therapy.2 However, the similarity of symptoms among patients does not imply common mechanisms, even when the cause of the pain is the same.3 For some patients, the pathophysiology of the mechanisms may primarily affect the peripheral nervous system, whereas for others the predominant mechanisms may affect the central nervous system.
The available therapies shown to be effective in managing neuropathic pain include anticonvulsant drugs, tricyclic antidepressant drugs, opioids, topical lidocaine, new antidepressant drugs such as duloxetine and venlafaxine, and the analgesic agent tramadol.4,5 The anticonvulsant drug gabapentin is used frequently to control pain in postherpetic neuralgia and diabetic neuropathy, on the basis of evidence of efficacy from randomized trials.6,7 The mechanism of action in gabapentin is unclear, but its effects on the 2 calcium-channel subunit may result in the decreased release of neurotransmitters and the suppression of central sensitization.
Opioids are also recommended as first-line treatment for neuropathic pain.5 Although their use was initially controversial, the benefits of opioids for neuropathic pain have been shown in studies of infused opioids, in a series of trials of oral medication, and even in comparison with alternative therapies.8 In a crossover study comparing opioids and tricyclic antidepressant drugs in patients with postherpetic neuralgia, we observed similar reductions in pain intensity with the use of opioids and antidepressants, but patients reported greater satisfaction with opioid therapy.9 Like the majority of opioid trials, our study used long-acting formulations and around-the-clock doses. The use of short-acting opioids is generally recommended only during an initial titration period or as an adjunct to the use of long-acting formulations to relieve breakthrough pain.
In the clinical management of neuropathic pain, when pain relief with gabapentin is incomplete, expert panels recommend adding a second analgesic agent, which may be an opioid. Until now, recommendations for combination therapy were based on theoretical mechanisms, rather than on controlled trials. In this issue of the Journal, Gilron et al.10 provide evidence of the efficacy of a combination of gabapentin and morphine in reducing pain and pain-related disability in patients with either diabetic neuropathy or postherpetic neuralgia. This double-blind, randomized, crossover trial compared monotherapy and combination therapy with active placebo (lorazepam). As in clinical practice, the study drugs were titrated with the objective of balancing analgesia and adverse effects. The combination treatment with morphine and gabapentin resulted in a greater reduction in pain than did gabapentin alone, morphine alone, or placebo. The combination therapy also had beneficial effects on pain-related interference with daily activities, mood, and health-related quality of life. The combination therapy resulted in a greater frequency of constipation than gabapentin alone did and a greater frequency of dry mouth than morphine alone did. The use of an active comparator drug is a particular strength of the trial design, and few patients (25 percent) correctly identified when they were receiving the gabapentin–morphine combination.
The titration procedure allowed the study nurse and the patients to find the best balance between analgesia and adverse effects. It probably contributed to the relatively low rate of adverse effects and enhances the generalizability of these findings to clinical care. With concurrent titration, patients stopped increasing the levels of gabapentin and morphine at lower doses of each agent when the two drugs were given in combination than they did when receiving each as monotherapy. As a result, treatment with the combination of gabapentin and morphine yielded greater reductions in pain and improvements in daily functioning with lower doses of each medication than each did alone.
Practical issues arise in applying these findings in clinical practice. For example, is combination therapy best given sequentially, as is typically recommended, or concurrently, as in the trial by Gilron et al.? Sequential therapy offers the opportunity to identify patients who do not respond to a single agent before the addition of a second agent. This may be especially valuable in treating patients with coexisting conditions that require multiple other medications or when drug interactions should be taken into account. However, the benefits of concurrent combination therapy shown in this study, including lower doses with greater pain relief and tolerable adverse effects, might be due to the simultaneous titration of the two drugs. The difference between recommended practice and the method of Gilron et al. deserves critical scrutiny in the future to determine whether sequential titration and concurrent titration of combination therapies yield different outcomes.
Since clinical trials often select patients who adhere maximally to study procedures and offer them considerable support during drug titration, actual adherence to combination therapy may be substantially lower in routine clinical settings. Unfortunately, little is known about adherence in the use of pain medications generally, but improved adherence to therapy with opioids does occur with a regular schedule of doses rather than with doses given as needed.11 Although a combined formulation was not used in this trial, such formulations may improve adherence, as has been shown with antiretroviral therapy.
Trials such as that conducted by Gilron and colleagues need to address additional challenges facing clinicians who are struggling to reduce neuropathic pain in the individual patient. For example, patients were satisfied with their pain relief and stopped increasing drug doses at an average pain level of 3 (on a scale from 0 to 10). How much pain, if any, is acceptable to patients who have chronic neuropathic pain? In deciding which treatment and which combination to use, does the response to a single agent predict the response to the combination? In deciding which treatment is appropriate to which patient, can preexisting patient characteristics, such as sex, genetic profile, and mechanisms underlying the persistent pain, predict the response to one agent as opposed to another? In deciding on combination therapy, do additive or synergistic effects occur with some combinations and not with others?
The study by Gilron et al. was not designed to test whether combination therapy is synergistic, or even additive. Preclinical studies, however, suggest a potential synergy between gabapentin and opioids.12 It is important to ascertain whether the lower drug doses obtained with the use of the combination therapy extend to reduced tolerance or the potential for abuse. Close examination of the data in the present study10 suggests that prior exposure to morphine may have reduced the beneficial effects of gabapentin. Identifying such subtleties in treatment response will require large-scale investigation.
As with various chronic conditions, the management of neuropathic pain remains challenging in many patients. This study clearly shows the advantages of concurrent titration of gabapentin and morphine, though the perceived risks of addiction and diversion with opioids and the fear of scrutiny by regulatory agencies may present barriers to the acceptance of this combination as first-line treatment. In addition to developing and testing new pharmacologic agents, we need clinical trials that will examine which drugs in which combination, used for which patients, provide effective pain relief with the lowest doses and tolerable adverse effects.
Supported in part by grants (NIH-NS26363, to Dr. Raja, and NIH-NS02225, to Dr. Haythornthwaite) from the National Institutes of Health.
Dr. Raja reports having received compensation from an unrestricted educational grant awarded by Pfizer to the Johns Hopkins University School of Medicine to develop a continuing medical education teaching module. Dr. Haythornthwaite reports having received a fee from Pfizer to review competitive grant applications for young investigators.
Source Information
From the Departments of Anesthesiology and Critical Care Medicine (S.N.R.) and Psychiatry and Behavioral Science (J.A.H.), Johns Hopkins University School of Medicine, Baltimore.
References
Woolf CJ. Dissecting out mechanisms responsible for peripheral neuropathic pain: implications for diagnosis and therapy. Life Sci 2004;74:2605-2610.
Woolf CJ, Decosterd I. Implications of recent advances in the understanding of pain pathophysiology for the assessment of pain in patients. Pain 1999;82:Suppl 1:S141-S147.
Fields HL, Rowbotham M, Baron R. Postherpetic neuralgia: irritable nociceptors and deafferentation. Neurobiol Dis 1998;5:209-227.
Chen H, Lamer TJ, Rho RH, et al. Contemporary management of neuropathic pain for the primary care physician. Mayo Clin Proc 2004;79:1533-1545.
Dworkin RH, Backonja M, Rowbotham MC, et al. Advances in neuropathic pain: diagnosis, mechanisms, and treatment recommendations. Arch Neurol 2003;60:1524-1534.
Rowbotham M, Harden N, Stacey B, Bernstein P, Magnus-Miller L. Gabapentin for the treatment of postherpetic neuralgia: a randomized controlled trial. JAMA 1998;280:1837-1842.
Backonja M, Beydoun A, Edwards KR, et al. Gabapentin for the symptomatic treatment of painful neuropathy in patients with diabetes mellitus: a randomized controlled trial. JAMA 1998;280:1831-1836.
Ballantyne JC, Mao J. Opioid therapy for chronic pain. N Engl J Med 2003;349:1943-1953.
Raja SN, Haythornthwaite JA, Pappagallo M, et al. Opioids versus antidepressants in postherpetic neuralgia: a randomized, placebo-controlled trial. Neurology 2002;59:1015-1021.
Gilron I, Bailey JM, Tu D, Holden RR, Weaver DF, Houlden RL. Morphine, gabapentin, or their combination for neuropathic pain. N Engl J Med 2005;352:1324-1334.
Miaskowski C, Dodd MJ, West C, et al. Lack of adherence with the analgesic regimen: a significant barrier to effective cancer pain management. J Clin Oncol 2001;19:4275-4279.
Eckhardt K, Ammon S, Hofmann U, Riebe A, Gugeler N, Mikus G. Gabapentin enhances the analgesic effect of morphine in healthy volunteers. Anesth Analg 2000;91:185-191.(Srinivasa N. Raja, M.D., )