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Efficacy and Safety of Opioid Agonists in the Treatment of Neuropathic Pain of Nonmalignant Origin:  Systematic Review and Meta-analysis of Randomized Controlled Trials FREE

Elon Eisenberg, MD; Ewan D. McNicol, RPh; Daniel B. Carr, MD
[+] Author Affiliations

Author Affiliations: Pain Relief Unit, Rambam Medical Center, and Haifa Pain Research Group, the Technion-Israel Institute of Technology, Haifa, Israel (Dr Eisenberg); Department of Anesthesia (Mr McNicol and Dr Carr), Pharmacy Department (Mr McNicol), and Division of Clinical Care Research (Dr Carr), Tufts–New England Medical Center and Tufts University School of Medicine, Boston, Mass. Dr Carr is now with Innovative Drug Delivery Systems Inc, New York, NY.

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JAMA. 2005;293(24):3043-3052. doi:10.1001/jama.293.24.3043.
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Published online

Context In the United States, an estimated 2 million persons have neuropathic pain that is often resistant to therapy. The use of opioids for neuropathic pain remains controversial, in part because studies have been small, have yielded equivocal results, and have not established the long-term risk-benefit ratio of this treatment.

Objective To assess the efficacy and safety of opioid agonists for the treatment of neuropathic pain based on published randomized controlled trials (RCTs).

Data Sources We searched MEDLINE (1966 to December 2004) and the Cochrane Central Register of Controlled Trials (fourth quarter, 2004) for articles in any language, along with reference lists of reviews and retrieved articles, using a combination of 9 search terms for RCTs with 32 terms for opioids and 15 terms for neuropathic pain.

Study Selection Trials were included in which opioid agonists were given to treat central or peripheral neuropathic pain of any etiology, pain was assessed using validated instruments, and adverse events were reported. Studies in which drugs other than opioid agonists were combined with opioids or opioids were administered epidurally or intrathecally were excluded.

Data Extraction Data were extracted by 2 independent investigators and included demographic variables, diagnoses, interventions, efficacy, and adverse effects.

Data Synthesis Twenty-two articles met inclusion criteria and were classified as short-term (less than 24 hours; n = 14) or intermediate-term (median = 28 days; range = 8-56 days; n = 8) trials. The short-term trials had contradictory results. In contrast, all 8 intermediate-term trials demonstrated opioid efficacy for spontaneous neuropathic pain. A fixed-effects model meta-analysis of 6 intermediate-term studies showed mean posttreatment visual analog scale scores of pain intensity after opioids to be 14 units lower on a scale from 0 to 100 than after placebo (95% confidence interval [CI], −18 to −10; P<.001). According to number needed to harm (NNH), the most common adverse event was nausea (NNH, 3.6; 95% CI, 2.9-4.8), followed by constipation (NNH, 4.6; 95% CI, 3.4-7.1), drowsiness (NNH, 5.3; 95% CI, 3.7-8.3), vomiting (NNH, 6.2; 95% CI, 4.6-11.1), and dizziness (NNH, 6.7; 95% CI, 4.8-10.0).

Conclusions Short-term studies provide only equivocal evidence regarding the efficacy of opioids in reducing the intensity of neuropathic pain. Intermediate-term studies demonstrate significant efficacy of opioids over placebo for neuropathic pain, which is likely to be clinically important. Reported adverse events of opioids are common but not life-threatening. Further RCTs are needed to establish their long-term efficacy, safety (including addiction potential), and effects on quality of life.

Figures in this Article

In the United States, an estimated 2 million persons have neuropathic pain.1 This may result from a large variety of insults to the peripheral or central somatosensory nervous system, including trauma, inflammation, ischemia, and metabolic and neoplastic disorders. Common examples of peripheral neuropathic pain include diabetic neuropathy, postherpetic neuralgia (PHN), and trigeminal neuralgia. Central neuropathic pain includes central poststroke pain, pain in multiple sclerosis, and post–spinal cord injury pain. The main clinical characteristics of neuropathic pain are continuous or intermittent spontaneous pain, typically described as burning, aching, or shooting in quality, and abnormal sensitivity of the painful site to normally innocuous stimuli such as light touch by garments, running water, or even wind (allodynia).2 Neuropathic pain, like many other forms of chronic pain, often has negative effects on quality of life. Pharmacotherapy of neuropathic pain has generally involved the use of antidepressants or anticonvulsants, but even with the current generation of these drugs, effective analgesia is achieved in less than half of this population.3

Clinical trials to assess the efficacy of opioids for reducing neuropathic pain have been reported for more than 15 years. Yet large variability in trial design in terms of the type of the neuropathic pain syndrome treated, the type of opioid administered, and the duration of treatment has yielded contradictory results. Studies that have suggested efficacy have had small study populations, raising questions about the validity of the results. Lack of definitive evidence regarding the efficacy of opioids in reducing neuropathic pain in general, and central neuropathic pain in particular, as well as concerns about adverse effect profiles and potential for abuse, addiction, hormonal abnormalities, dysfunction of the immune system, and, in some cases, paradoxical hyperalgesia,48 discourage use of opioids in the treatment of neuropathic pain.9

Given growing interest in and concerns regarding prescribing of opioids to patients with neuropathic pain, we conducted a systematic review of published randomized controlled trials (RCTs) to answer 2 questions: (1) What is the efficacy of opioid agonists in relieving neuropathic pain? and (2) What is the nature and occurrence of adverse effects caused by opioid agonists in patients with neuropathic pain?

Search Strategy

We searched for pertinent articles in any language using the MEDLINE database (1966 to December 2004), the Cochrane Central Register of Controlled Trials (fourth quarter, 2004), and the reference lists of reviews and retrieved articles. We did not contact authors for original data and did not consider abstracts or unpublished reports. We combined 9 search terms for RCTs with 32 terms for opioids and 15 terms for neuropathic pain.

Inclusion and Exclusion Criteria

We reviewed abstracts of all citations and retrieved studies based on the following inclusion criteria: (1) design was randomized, blinded, controlled trial; (2) opioid agonists (but not partial agonists or agonist-antagonists) were given to treat central or peripheral neuropathic pain of any etiology; (3) 1 or more opioid agonists or different doses of the same opioid agonist were compared with placebo, each other, or another class of medications used for neuropathic pain (eg, antidepressants); (4) drugs were administered by any of the following routes: orally, rectally, transdermally, intravenously, intramuscularly, or subcutaneously; (5) neuropathic pain was assessed with validated pain measurement tools; and (6) adverse events were reported. Men and women of all ages and races/ethnicities were included.

We excluded studies in which (1) patients with both neuropathic and other types of pain (eg, nociceptive) were enrolled and responses of the 2 groups of patients were not differentiated; (2) drugs other than opioid agonists were combined with opioids (eg, codeine with acetaminophen); (3) opioids were administered epidurally or intrathecally; (4) tramadol was used as the active drug, because although tramadol interacts to some degree with opioid receptors, it is not regarded as a pure opioid agonist. The efficacy of tramadol in relieving neuropathic pain has been recently reviewed.10

Data Extraction

Information on study design, methods, interventions, pain outcomes, and adverse effects was extracted from each article. In addition, diagnoses, patient inclusion and exclusion criteria, numbers of patients enrolled and completing the study, and functional assessments were extracted into a standardized table by 2 independent investigators (E.E. and E.D.M.) who were not blinded to study authors. Discrepancies in extracted data were resolved by discussion prior to including data in the analysis.

Analyses focused on differences in pain intensity, pain relief, and the incidence and severity of adverse effects. When possible we normalized all data to a 0- to 100-mm visual analog scale (VAS). No attempt was made to convert surrogate outcomes (eg, global evaluations or preferences, amount of rescue medication used) to a VAS. For studies in which surrogate outcomes were the only results available, they are described herein as such. The number of patients experiencing adverse events was extracted from trials in which patients were asked about or observed for specific adverse effects, such as constipation. Withdrawals or dropouts were noted if described.

Assessment of Methodological Quality

Studies that met inclusion criteria were graded for methodological quality using a scale reported by Jadad et al.11 Jadad scores are based on the description of randomization, blinding, and withdrawals and can range from 0 to 5, where higher scores indicate better methodological quality.

Statistical Analysis

We performed statistical analyses of included trials using the Cochrane Collaboration’s Review Manager software (RevMan), version 4.2.7 (Oxford, England: Cochrane Collaboration). Whenever possible, results from the trials were combined to calculate differences in postintervention pain intensity or pain relief and to calculate relative risks (RRs) for adverse effects, along with 95% confidence intervals (CIs). We evaluated heterogeneity between and within trials using the χ2 test.12 Because studies that were combined appeared to be homogeneous, a fixed-effects model was used for all analyses. A funnel chart of the intermediate-term trials (Figure 1) was consistent with absence of publication bias. P values less than .05 were considered significant.

Figure 1. Funnel Plot of Intermediate-term Efficacy Studies
Graphic Jump Location

Plot shows standard error of effect estimate vs effect estimate for each study (fixed-effects model). Vertical dotted line indicates overall effect estimate; dashed lines, 95% confidence intervals; and dots, individual studies.

Overview of Included Studies

The literature search yielded 1995 citations, of which 44 were selected for retrieval. Twenty-two1334 of the 44 articles met inclusion criteria and provided data on 670 opioid-treated patients with neuropathic pain. We divided the trials into 2 categories according to study duration. The first group consisted of 14 short-term trials,1326 in which opioids were administered mostly as brief intravenous infusions and outcomes were measured for less than 24 hours. The number of patients in each of these studies was generally small (median, 13; range, 7-53). The second group consisted of 8 intermediate-term trials,2734 in which opioids were administered orally over longer periods, between 8 and 56 days (median, 28 days), generally to larger numbers of patients (median, 47; range, 12-157). A QUOROM (Quality of Reporting of Meta-analyses) flow diagram (Figure 2) shows an overview of the study selection process.

Figure 2. Flow Diagram of Included and Excluded Studies
Graphic Jump Location

RCT indicates randomized controlled trial.

Excluded Studies

Three controlled trials3537 of opioids for neuropathic pain failed to meet 1 or more of the inclusion criteria. First, an RCT conducted over 7 days35 compared morphine with placebo in a mixed group of patients with various neuropathic and nociceptive pain syndromes. The authors reported that “the number of responders was significantly higher in patients with neuropathic than with nociceptive pain.” However, efficacy and adverse effects of the 2 types of pain were combined into a single outcome, thereby precluding separate analyses of data for the 2 subgroups. That study was therefore excluded. Second, a short-term, placebo-controlled trial36 showed that only 4 of the 14 tested patients with multiple sclerosis and central neuropathic pain were categorized as “responders” to intravenous morphine. The study was nonrandomized and single-blinded. Third, in an RCT,37 5 different doses of buprenorphine (0.033-0.166 mg) were randomly administered to 21 patients with postthoracotomy neuropathic pain 1 month after surgery, with reduction of pain by 50% in each of the patients. However, buprenorphine is a partial μ receptor agonist, with different pharmacological properties than those of the full μ opioid agonist class.

Study Quality

The quality of the short- and intermediate-term studies as judged by the Jadad score is presented in Table 1 and Table 2, respectively. The median overall score was 4 (range, 2-5) indicating generally good methodological quality. The Jadad scores of intermediate-term studies were nonsignificantly higher than those of short-term studies (median, 5 vs 4). Inadequate description of the randomization process (in 8 trials) was the most common shortfall in the short-term trials. In the intermediate-term trials, 6 trials scored 5 points, 1 scored 3,28 and 1 scored 2.29 Inadequate description of adverse events, reasons for dropout, methods of randomization, and blinding led to the lower scores of the latter 2 studies.

Table Graphic Jump LocationTable 1. Short-term RCTs of Treatment of Neuropathic Pain: Design, Quality Assessment, and Effects of Opioids vs Placebo on Spontaneous Pain
Table Graphic Jump LocationTable 2. Intermediate-term Studies: Design, Quality Assessment, and Outcome of Treatmenta
Short-term Studies

Fourteen RCTs using a crossover design provided adequate data regarding efficacy of acute exposure to opioids in 267 patients with neuropathic pain (Table 1). Drugs were administered intravenously in 12 trials, orally in 1 trial,26 and intramuscularly in 1 trial.17 The duration of treatment varied from seconds (ie, a single intramuscular injection) to 8 hours but was less than 1 hour in 10 trials. The tested drug was morphine in 7 trials, alfentanil in 4 trials, and fentanyl, meperidine, or codeine in 1 trial each. Placebo was used as a control in 12 trials. The diagnosis was specified in all trials: 3 trials studied patients with PHN only,21,23,26 2 studied patients with posttraumatic neuralgia,13,19 5 studied patients with mixed neuropathies,16,18,22,24,25 2 studied patients with central pain,14,20 1 studied patients with secondary (eg, posttraumatic) trigeminal neuropathy,17 and 1 enrolled patients with postamputation stump and phantom pain.15 Considerable variation between studies in dosages, durations of treatment, and methods of pain assessment allowed only limited quantitative synthesis of data.

Change in spontaneous pain intensity was the primary outcome measure in all 14 trials (Table 1). Mixed results were found with respect to the analgesic efficacy of opioids for neuropathic pain in general and for specific conditions (ie, PHN, posttraumatic neuralgia, and central pain). Six trials showed greater efficacy of the tested opioid than of placebo.13,15,16,18,20,23 In contrast, 5 trials observed equivalent efficacy for opioids and placebo.14,19,21,25,26 Partial efficacy, meaning that some patients responded to the opioid treatment while others did not, was reported in 2 trials.17,22 Another trial reported reduction in the affective but not in the sensory component of pain.24

Data from 4 articles (comprising 6 trials) with a total of 90 patients were combinable for a meta-analysis,14,15,23,24 since they reported means and standard deviations for pain intensity after active drug or placebo. The χ2 test for heterogeneity was 0.58 (P = .99), indicating a high degree of homogeneity between and within studies. Opioid treatment was superior to placebo in all trials but reached statistical significance in only 3 trials (Figure 3). The overall mean difference in the last measured pain intensity for active treatment vs placebo was −16 (on a 0-100 VAS) (95% CI, −23 to −9; P<.001). Data from 2 trials in a total of 21 patients with central pain and from 4 trials in 69 patients with peripheral neuropathic pain were combinable for a further meta-analysis. For peripheral pain, the final pain intensity following opioid administration was 15 points lower than that after placebo (95% CI, −23 to −7; P<.001), whereas for central pain, the difference was 18 points (95% CI, −30 to −5; P = .006) (Figure 3). When categorized according to etiology (eg, posttraumatic neuralgia,13,19 PHN21,23,26), the results were equivocal. One within-study comparison22 and 2 other between-study comparisons (Jorum et al13 vs Max et al19 and Eide et al21 vs Rowbotham et al23) of high vs low opioid doses did not show an association between the opioid dose administered and analgesic efficacy.

Figure 3. Results of the Meta-analysis of Short-term Trial Efficacy
Graphic Jump Location

Data are presented as mean (95% confidence interval [CI]) differences in last measured posttreatment pain intensity (on a visual analog scale from 0-100) between active treatment and placebo (fixed-effects model). Size of the data markers corresponds to the weight of the study in the meta-analysis.

Intermediate-term Studies

Eight trials provided data on 403 opioid-treated patients (Table 2). The number of patients per treatment group ranged from 12 to 82 and the duration of treatment varied from 8 days to 8 weeks (median, 28 days). Five trials had a crossover design and 3 had a parallel design. Four drugs were tested: morphine and oxycodone, each in 3 trials; methadone in 1 article comprising 2 trials; and levorphanol in 1 trial. Placebo was used as a control in all but 1 trial.34 In 2 trials, additional study groups in which patients were administered nonopioid active drugs were included for comparison: carbamazepine in 1 trial29 and the tricyclic antidepressants nortriptyline and desipramine in 1 trial.30 Two trials compared different dosages of an opioid: 1 compared 2 different dosages of methadone33 and 1 compared 2 different dosages of levorphanol.34 Five trials enrolled patients with 1 specific pain syndrome: diabetic neuropathy,31,32 PHN,27,30 and phantom pain.28 The other 3 studies enrolled patients with neuropathic pain of diverse etiologies.

All trials reported that opioids were efficacious in reducing spontaneous neuropathic pain by demonstrating either superiority over placebo or a dose-dependent analgesic response. Six of the 8 studies provided data suitable for pooling based on data on pain intensity after active drug and placebo treatments. The χ2 test did not suggest that the data were heterogeneous (χ2 = 6.34; P = .27). The meta-analysis included 263 opioid- and 258 placebo-treated patients and found overall mean pain intensity to be 14 points lower in opioid-treated patients than in those treated with placebo (95% CI, −18 to −10; P<.001; Figure 4). A post hoc subanalysis of the highest-quality trials was performed, excluding 1 study28 with a Jadad score of 3. The new estimate of the difference between VAS values in the opioid and placebo groups for the remaining 5 studies was −15(95% CI, −19 to −11).

Figure 4. Results of the Meta-analysis of Intermediate-term Trial Efficacy
Graphic Jump Location

Data are presented as mean (95% confidence interval [CI]) differences in posttreatment pain intensity (on a visual analog scale from 0-100) between active treatment and placebo (fixed-effects model). Size of the data markers corresponds to the weight of the study in the meta-analysis.

Dose-dependent analgesic effect was found in 2 studies33,34 that included patients with mixed neuropathies. In 1 study,33 low and high doses of methadone were each compared separately with placebo, and the higher dose produced a larger effect than the lower dose. In the other study,34 a direct comparison showed that a high dose of levorphanol produced a significantly larger analgesic effect than the lower dose. The use of different outcome measures in the 2 studies precluded the performance of dose-response meta-analysis. Evoked pain was measured in only 2 studies.27,32 In both trials, oxycodone was significantly superior to placebo in reducing allodynia, categorized as “skin pain.”

Six of the 8 trials measured the effects of opioids on secondary outcome parameters, such as disability, sleep, cognition, and depression. However, because of the use of 20 different measurement tools, these trials’ data could not be quantitatively combined. These findings are summarized in Table 2. Both the physical and mental health components of the Short Form-36 were improved by oxycodone treatment to a greater degree than placebo in patients with diabetic neuropathy in one study32 but not in another.31 In patients with PHN, neither the Multidimensional Pain Inventory30 nor the Categorical Disability Scale27 showed improvement with oxycodone treatment. Thus, no consistent reduction in disability was found. Depression, measured by the Beck Depression Inventory and by the Profile of Mood States Questionnaire (POMS), failed to improve with oxycodone treatment in patients with PHN.27 Similarly, no improvement was noted in the POMS scores of patients with mixed neuropathies treated with 2 different dosages of levorphanol34 nor in the RAND Mental Health Inventory completed by patients with diabetic neuropathy following oxycodone treatment.31

Adverse Events and Withdrawals Due to Adverse Events

Although data on the prevalence of common opioid-related adverse effects were extracted from all studies, the majority of information was obtained from 5 intermediate-term placebo-controlled trials2933 and a lesser amount from 2 additional studies.27,34 Another study28 reported adverse events on a VAS scale, precluding determination of the numbers of affected patients (Table 3). Whenever possible, we calculated number needed to harm38 (NNH) for each of the common opioid adverse effects. To avoid the possibility that NNH might have been biased due to selective dropout of patients experiencing adverse effects, we included only studies in which the adverse event that led to the patient’s withdrawal was specified. The most common adverse effect was nausea (NNH, 3.6; 95% CI, 2.9-4.8), followed by constipation (NNH, 4.6; 95% CI, 3.4-7.1), drowsiness (NNH, 5.3; 95% CI, 3.7-8.3), vomiting (NNH, 6.2; 95% CI, 4.6-11.1), and dizziness (NNH, 6.7; 95% CI, 4.8-10.0). Data on cognitive impairment as well as on other adverse effects were insufficient to allow calculation of NNH.

Table Graphic Jump LocationTable 3. Adverse Events in RCTs of Opioid Treatment of Neuropathic Pain

When opioid therapy is initiated, there is always a possibility that patients will abandon treatment because of adverse events. Of the 8 intermediate-term RCTs reviewed, 4 trials provided combinable information regarding the number of dropouts due to adverse events.3134 In total, 33 (13.5%) of 244 patients in these 4 studies withdrew because of adverse events during opioid therapy vs 12 (7.6%) of 158 patients receiving placebo.

The results of this study can be divided into 2 categories according to the duration of included trials. Short-term trials yielded mixed results with respect to the analgesic efficacy of opioids. Intermediate-term trials demonstrated consistent opioid analgesic efficacy in reducing spontaneous neuropathic pain that was statistically significant when their results were pooled. These larger trials are more clinically relevant than the shorter ones because they assess the benefits and risks associated with opioid treatments for weeks to months.

This study included trials that assessed outcomes using diverse scales and often presented them in ways that made accurate extraction of raw data impossible. Because of this, results of many of the studies, and, in particular, the short-term studies, could not be included in our quantitative analyses. The problem of heterogeneity of outcomes in the published literature on pain,39 including neuropathic pain,40 has been described and has compelled systematic reviews of analgesic interventions to adopt a “best available evidence” approach.41,42 Any conclusions from our meta-analyses of short-term trials should be interpreted with caution because they are based on only 4 of 14 studies (and only 90 of 267 treated patients), all of which showed positive results.

In contrast with the short-term trials, the meta-analysis of intermediate-term studies was based on most of the available trials and included the majority of treated patients. Furthermore, the 2 studies not included in the meta-analysis because of noncombinable data also found benefit from opioids over placebo. Hence, we conclude that intermediate-term opioid treatment has a beneficial effect over placebo for spontaneous neuropathic pain for up to 8 weeks of treatment and that the magnitude of this opioid effect is a nearly 14-point difference in pain intensity at study end compared with placebo. A 14-point difference out of 100 points can be compared with that achieved by other commonly used treatments for neuropathic pain. For example, the equivalent pain intensity at study end with gabapentin treatment would be 12 points lower than placebo (39 vs 51) in patients with painful diabetic neuropathy.43 To achieve this effect, 67% of the patients in the gabapentin study required the maximal daily dose (3600 mg), whereas in the opioid studies a larger effect was achieved by a low to moderate dose of opioid. The dose-dependent analgesic effect shown in 2 of the opioid studies33,34 suggests that higher doses of opioids may have the potential to produce a greater magnitude of pain reduction in patients with neuropathic pain. Yet, for the most part, patients in the trials received opioids within a relatively narrow range of fixed doses. Our meta-analysis suggests that a goal of future studies in this area should be to evaluate true efficacy of opioids for neuropathic pain by means of trials with wider dose ranges rather than fixed-dose studies.

A challenging question is whether an average decline of 14 points on a scale of 0 to 100 is meaningful for patients. The mean initial pain intensity was recorded from the patients in 4 of the intermediate-term trials and ranged from 46 to 69. This 14-point difference therefore corresponds to a 20% to 30% greater reduction of neuropathic pain with opioids than with placebo. Analysis of data from large randomized clinical trials has shown that 30% reduction in pain intensity may be the threshold for patients to describe a reduction in chronic pain as meaningful.4446

Correlations between the response to a brief exposure to local anesthetics and N-methyl-D-aspartate receptor antagonists and long-term response to their oral analogues have been reported.4749 The difference in outcomes between short-term and intermediate-term opioid studies does not support a similar use of short-term opioid administration as a predictive tool to decide whether to initiate intermediate-term opioid therapy.

The debate regarding the differential efficacy of opioids for central vs peripheral pain48 has not been resolved by our study. Results of the included studies varied considerably and the meta-analyses could not include all relevant studies. Despite limited data, the meta-analyses showed similar opioid responsiveness for pain of central and peripheral etiologies.

This study also included a quantitative analysis of common opioid-related adverse effects.50 Although the analysis is based on a relatively large number of patients with neuropathic pain, patients enrolled in clinical trials may not be representative of the broader patient population seen in clinical practice. Enrolled patients have met inclusion criteria, and their willingness to enter a clinical trial suggests that they may have a higher adherence profile compared with unselected patients.

Two other limitations of this systematic review result from the design of the included studies. First, the duration of studies was at most 8 weeks. Therefore, we do not have data on the efficacy or adverse event rate of opioids in the treatment of neuropathic pain over months to years. Second, the available RCTs do not clearly address the issues of addiction and abuse. The absence of any report of addictive behavior or abuse in any of intermediate-term trials may have several explanations. It is possible that the prevalence of these behaviors is indeed low.51 Alternatively, the duration of treatment in these studies may have been too short to allow such behaviors to develop. Furthermore, although not mentioned specifically as an exclusion criterion, it is reasonably likely that recruitment of patients with apparent abuse or addiction potential52 into such studies would often be avoided. The need to further assess the risk of abuse and addiction continues to be important.

Finally, the management of any form of chronic pain requires not only reduction in pain intensity but also improved quality of life in dimensions such as sleep, mood, work, social, and recreational capacities.53 Unfortunately, because of the use of a large number of measurement tools in the included trials, these results could not be quantitatively combined and no consistent improvement in quality of life could be demonstrated. Our meta-analysis takes an initial and necessary first step of showing efficacy for spontaneous pain during opioid treatment for up to 2 months. Further RCTs assessing longer-term efficacy, safety (including addiction potential), and improved quality of life should be undertaken before the value of opioids for management of neuropathic pain is finally established.

Corresponding Author: Elon Eisenberg, MD, Pain Relief Unit, Rambam Medical Center, PO Box 9602, Haifa 31096, Israel (e_eisenberg@rambam.health.gov.il).

Author Contributions: Dr Eisenberg had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Eisenberg, Carr.

Acquisition of data: Eisenberg, McNicol.

Analysis and interpretation of data: Eisenberg, McNicol, Carr.

Drafting of the manuscript: Eisenberg, McNicol.

Critical revision of the manuscript for important intellectual content: Eisenberg, McNicol, Carr.

Statistical analysis: Eisenberg, McNicol.

Administrative, technical, or material support: Eisenberg, Carr.

Study supervision: Eisenberg.

Financial Disclosures: Dr Carr is now with Innovative Drug Delivery Systems Inc, a small specialty pharmaceutical company with no products yet marketed. None of the other authors reported disclosures.

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Jadad AR, Carroll D, Glynn CJ, Moore RA, McQuay HJ. Morphine responsiveness of chronic pain: double-blind randomised crossover study with patient-controlled analgesia.  Lancet. 1992;339:1367-1371
PubMed   |  Link to Article
Rowbotham MC, Reisner-Keller LA, Fields HL. Both intravenous lidocaine and morphine reduce the pain of postherpetic neuralgia.  Neurology. 1991;41:1024-1028
PubMed   |  Link to Article
Kupers RC, Konings H, Adriaensen H, Gybels JM. Morphine differentially affects the sensory and affective pain ratings in neurogenic and idiopathic forms of pain.  Pain. 1991;47:5-12
PubMed   |  Link to Article
Arner S, Meyerson BA. Lack of analgesic effect of opioids on neuropathic and idiopathic forms of pain.  Pain. 1988;33:11-23
PubMed   |  Link to Article
Max MB, Schafer SC, Culnane M, Dubner R, Gracely RH. Association of pain relief with drug side effects in postherpetic neuralgia: a single-dose study of clonidine, codeine, ibuprofen, and placebo.  Clin Pharmacol Ther. 1988;43:363-371
PubMed   |  Link to Article
Watson CP, Babul N. Efficacy of oxycodone in neuropathic pain: a randomized trial in postherpetic neuralgia.  Neurology. 1998;50:1837-1841
PubMed   |  Link to Article
Huse E, Larbig W, Flor H, Birbaumer N. The effect of opioids on phantom limb pain and cortical reorganization.  Pain. 2001;90:47-55
PubMed   |  Link to Article
Harke H, Gretenkort P, Ladleif HU, Rahman S, Harke O. The response of neuropathic pain and pain in complex regional pain syndrome I to carbamazepine and sustained-release morphine in patients pretreated with spinal cord stimulation: a double-blinded randomized study.  Anesth Analg. 2001;92:488-495
PubMed   |  Link to Article
Raja SN, Haythornthwaite JA, Pappagallo M.  et al.  Opioids versus antidepressants in postherpetic neuralgia: a randomized, placebo-controlled trial.  Neurology. 2002;59:1015-1021
PubMed   |  Link to Article
Gimbel JS, Richards P, Portenoy RK. Controlled-release oxycodone for pain in diabetic neuropathy: a randomized controlled trial.  Neurology. 2003;60:927-934
PubMed   |  Link to Article
Watson CP, Moulin D, Watt-Watson J, Gordon A, Eisenhoffer J. Controlled-release oxycodone relieves neuropathic pain: a randomized controlled trial in painful diabetic neuropathy.  Pain. 2003;105:71-78
PubMed   |  Link to Article
Morley JS, Bridson J, Nash TP, Miles JB, White S, Makin MK. Low-dose methadone has an analgesic effect in neuropathic pain: a double-blind randomized controlled crossover trial.  Palliat Med. 2003;17:576-587
PubMed   |  Link to Article
Rowbotham MC, Twilling L, Davies PS, Reisner L, Taylor K, Mohr D. Oral opioid therapy for chronic peripheral and central neuropathic pain.  N Engl J Med. 2003;348:1223-1232
PubMed   |  Link to Article
Maier C, Hildebrandt J, Klinger R, Henrich-Eberl C, Lindena G.MONTAS Study Group.  Morphine responsiveness, efficacy and tolerability in patients with chronic non-tumor associated pain: results of a double-blind placebo-controlled trial (MONTAS).  Pain. 2002;97:223-233
PubMed   |  Link to Article
Kalman S, Osterberg A, Sorensen J, Boivie J, Bertler A. Morphine responsiveness in a group of well-defined multiple sclerosis patients: a study with i.v. morphine.  Eur J Pain. 2002;6:69-80
PubMed   |  Link to Article
Benedetti F, Vighetti S, Amanzio M.  et al.  Dose-response relationship of opioids in nociceptive and neuropathic postoperative pain.  Pain. 1998;74:205-211
PubMed   |  Link to Article
Cook RJ, Sackett DL. The number needed to treat: a clinically useful measure of treatment effect.  BMJ. 1995;310:452-454
PubMed   |  Link to Article
Carr DB, Goudas LC, Balk EM, Bloch R, Ioannidis JP, Lau J. Evidence report on the treatment of pain in cancer patients.  J Natl Cancer Inst Monogr. 2004;32:23-31
PubMed   |  Link to Article
Stanton-Hicks MD, Burton AW, Bruehl SP.  et al.  An updated interdisciplinary clinical pathway for CRPS: report of an expert panel.  Pain Pract. 2002;2:1-16
Link to Article
McNicol E, Strassels S, Goudas L, Lau J, Carr D. Nonsteroidal anti-inflammatory drugs, alone or combined with opioids, for cancer pain: a systematic review.  J Clin Oncol. 2004;22:1975-1992
PubMed   |  Link to Article
Mailis A, Furlan A. Sympathectomy for neuropathic pain.  Cochrane Database Syst Rev. 2003;(2):CD002918
PubMed
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
PubMed   |  Link to Article
Farrar JT, Portenoy RK, Berlin JA, Kinman JL, Strom BL. Defining the clinically important difference in pain outcome measures.  Pain. 2000;88:287-294
PubMed   |  Link to Article
Cepeda MS, Africano JM, Polo R, Alcala R, Carr DB. What decline in pain intensity is meaningful to patients with acute pain?  Pain. 2003;105:151-157
PubMed   |  Link to Article
Farrar JT, Young JP Jr, LaMoreaux L, Werth JL, Poole RM. Clinical importance of changes in chronic pain intensity measured on an 11-point numerical pain rating scale.  Pain. 2001;94:149-158
PubMed   |  Link to Article
Galer BS, Harle J, Rowbotham MC. Response to intravenous lidocaine infusion predicts subsequent response to oral mexiletine: a prospective study.  J Pain Symptom Manage. 1996;12:161-167
PubMed   |  Link to Article
Attal N, Rouaud J, Brasseur L, Chauvin M, Bouhassira D. Systemic lidocaine in pain due to peripheral nerve injury and predictors of response.  Neurology. 2004;62:218-225
PubMed   |  Link to Article
Cohen SP, Chang AS, Larkin T, Mao J. The intravenous ketamine test: a predictive response tool for oral dextromethorphan treatment in neuropathic pain.  Anesth Analg. 2004;99:1753-1759
PubMed   |  Link to Article
McNicol E, Horowicz-Mehler N, Fisk RA.  et al.  Management of opioid side effects in cancer-related and chronic noncancer pain: a systematic review.  J Pain. 2003;4:231-256
PubMed
Sullivan M, Ferrell B. Ethical challenges in the management of chronic nonmalignant pain: negotiating through the cloud of doubt.  J Pain. 2005;6:2-9
PubMed   |  Link to Article
Dunbar SA, Katz NP. Chronic opioid therapy for nonmalignant pain in patients with a history of substance abuse: report of 20 cases.  J Pain Symptom Manage. 1996;11:163-171
PubMed   |  Link to Article
Wittick H, Carr DBPain Management: Evidence, Outcomes and Quality of Life: A Sourcebook. Amsterdam, the Netherlands: Elsevier; 2005

Figures

Figure 1. Funnel Plot of Intermediate-term Efficacy Studies
Graphic Jump Location

Plot shows standard error of effect estimate vs effect estimate for each study (fixed-effects model). Vertical dotted line indicates overall effect estimate; dashed lines, 95% confidence intervals; and dots, individual studies.

Figure 2. Flow Diagram of Included and Excluded Studies
Graphic Jump Location

RCT indicates randomized controlled trial.

Figure 3. Results of the Meta-analysis of Short-term Trial Efficacy
Graphic Jump Location

Data are presented as mean (95% confidence interval [CI]) differences in last measured posttreatment pain intensity (on a visual analog scale from 0-100) between active treatment and placebo (fixed-effects model). Size of the data markers corresponds to the weight of the study in the meta-analysis.

Figure 4. Results of the Meta-analysis of Intermediate-term Trial Efficacy
Graphic Jump Location

Data are presented as mean (95% confidence interval [CI]) differences in posttreatment pain intensity (on a visual analog scale from 0-100) between active treatment and placebo (fixed-effects model). Size of the data markers corresponds to the weight of the study in the meta-analysis.

Tables

Table Graphic Jump LocationTable 1. Short-term RCTs of Treatment of Neuropathic Pain: Design, Quality Assessment, and Effects of Opioids vs Placebo on Spontaneous Pain
Table Graphic Jump LocationTable 2. Intermediate-term Studies: Design, Quality Assessment, and Outcome of Treatmenta
Table Graphic Jump LocationTable 3. Adverse Events in RCTs of Opioid Treatment of Neuropathic Pain

References

Foley KM. Opioids and chronic neuropathic pain.  N Engl J Med. 2003;348:1279-1281
PubMed   |  Link to Article
Yarnitsky D, Eisenberg E. Neuropathic pain: between positive and negative ends.  Pain Forum. 1998;7:241-242
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Sindrup SH, Jensen TS. Efficacy of pharmacological treatments of neuropathic pain: an update and effect related to mechanism of drug action.  Pain. 1999;83:389-400
PubMed   |  Link to Article
McQuay HJ. Opioid use in chronic pain.  Acta Anaesthesiol Scand. 1997;41:175-183
PubMed   |  Link to Article
Dellemijn P. Are opioids effective in relieving neuropathic pain?  Pain. 1999;80:453-462
PubMed   |  Link to Article
Canavero S, Bonicalzi V. Chronic neuropathic pain.  N Engl J Med. 2003;348:2688-2689
PubMed   |  Link to Article
Ballantyne JC, Mao J. Opioid therapy for chronic pain.  N Engl J Med. 2003;349:1943-1953
PubMed   |  Link to Article
Nicholson BD. Evaluation and treatment of central pain syndromes.  Neurology. 2004;62:(suppl 2)  S30-S36
PubMed   |  Link to Article
Carver A, Foley K. Facts and an open mind should guide clinical practice.  Curr Neurol Neurosci Rep. 2001;1:97-98
PubMed   |  Link to Article
Duhmke RM, Cornblath DD, Hollingshead JR. Tramadol for neuropathic pain.  Cochrane Database Syst Rev. 2004;(2):CD003726
PubMed
Jadad AR, Moore RA, Carroll D.  et al.  Assessing the quality of reports of randomized clinical trials: is blinding necessary?  Control Clin Trials. 1996;17:1-12
PubMed   |  Link to Article
Clarke M, Oxman ADAnalysing and Presenting Results: Cochrane Reviewers’ Handbook 4.2 [updated November 2002]. Section 8. In: The Cochrane Library [database on disk and CD-ROM]. Oxford: Update Software; 2003:issue 1
Jorum E, Warncke T, Stubhaug A. Cold allodynia and hyperalgesia in neuropathic pain: the effect of N-methyl-D-aspartate (NMDA) receptor antagonist ketamine: a double-blind, cross-over comparison with alfentanil and placebo.  Pain. 2003;101:229-235
PubMed   |  Link to Article
Attal N, Guirimand F, Brasseur L, Gaude V, Chauvin M, Bouhassira D. Effects of IV morphine in central pain: a randomized placebo-controlled study.  Neurology. 2002;58:554-563
PubMed   |  Link to Article
Wu CL, Tella P, Staats PS.  et al.  Analgesic effects of intravenous lidocaine and morphine on postamputation pain: a randomized double-blind, active placebo-controlled, crossover trial.  Anesthesiology. 2002;96:841-848
PubMed   |  Link to Article
Leung A, Wallace MS, Ridgeway B, Yaksh T. Concentration-effect relationship of intravenous alfentanil and ketamine on peripheral neurosensory thresholds, allodynia and hyperalgesia of neuropathic pain.  Pain. 2001;91:177-187
PubMed   |  Link to Article
Rabben T, Skjelbred P, Oye I. Prolonged analgesic effect of ketamine, an N-methyl-D-aspartate receptor inhibitor, in patients with chronic pain.  J Pharmacol Exp Ther. 1999;289:1060-1066
PubMed
Dellemijn PL, Vanneste JA. Randomised double-blind active-placebo-controlled crossover trial of intravenous fentanyl in neuropathic pain.  Lancet. 1997;349:753-758
PubMed   |  Link to Article
Max MB, Byas-Smith MG, Gracely RH, Bennett GJ. Intravenous infusion of the NMDA antagonist, ketamine, in chronic posttraumatic pain with allodynia: a double-blind comparison to alfentanil and placebo.  Clin Neuropharmacol. 1995;18:360-368
PubMed   |  Link to Article
Eide PK, Stubhaug A, Stenehjem AE. Central dysesthesia pain after traumatic spinal cord injury is dependent on N-methyl-D-aspartate receptor activation.  Neurosurgery. 1995;37:1080-1087
PubMed   |  Link to Article
Eide PK, Jorum E, Stubhaug A, Bremnes J, Breivik H. Relief of post-herpetic neuralgia with the N-methyl-D-aspartic acid receptor antagonist ketamine: a double-blind, cross-over comparison with morphine and placebo.  Pain. 1994;58:347-354
PubMed   |  Link to Article
Jadad AR, Carroll D, Glynn CJ, Moore RA, McQuay HJ. Morphine responsiveness of chronic pain: double-blind randomised crossover study with patient-controlled analgesia.  Lancet. 1992;339:1367-1371
PubMed   |  Link to Article
Rowbotham MC, Reisner-Keller LA, Fields HL. Both intravenous lidocaine and morphine reduce the pain of postherpetic neuralgia.  Neurology. 1991;41:1024-1028
PubMed   |  Link to Article
Kupers RC, Konings H, Adriaensen H, Gybels JM. Morphine differentially affects the sensory and affective pain ratings in neurogenic and idiopathic forms of pain.  Pain. 1991;47:5-12
PubMed   |  Link to Article
Arner S, Meyerson BA. Lack of analgesic effect of opioids on neuropathic and idiopathic forms of pain.  Pain. 1988;33:11-23
PubMed   |  Link to Article
Max MB, Schafer SC, Culnane M, Dubner R, Gracely RH. Association of pain relief with drug side effects in postherpetic neuralgia: a single-dose study of clonidine, codeine, ibuprofen, and placebo.  Clin Pharmacol Ther. 1988;43:363-371
PubMed   |  Link to Article
Watson CP, Babul N. Efficacy of oxycodone in neuropathic pain: a randomized trial in postherpetic neuralgia.  Neurology. 1998;50:1837-1841
PubMed   |  Link to Article
Huse E, Larbig W, Flor H, Birbaumer N. The effect of opioids on phantom limb pain and cortical reorganization.  Pain. 2001;90:47-55
PubMed   |  Link to Article
Harke H, Gretenkort P, Ladleif HU, Rahman S, Harke O. The response of neuropathic pain and pain in complex regional pain syndrome I to carbamazepine and sustained-release morphine in patients pretreated with spinal cord stimulation: a double-blinded randomized study.  Anesth Analg. 2001;92:488-495
PubMed   |  Link to Article
Raja SN, Haythornthwaite JA, Pappagallo M.  et al.  Opioids versus antidepressants in postherpetic neuralgia: a randomized, placebo-controlled trial.  Neurology. 2002;59:1015-1021
PubMed   |  Link to Article
Gimbel JS, Richards P, Portenoy RK. Controlled-release oxycodone for pain in diabetic neuropathy: a randomized controlled trial.  Neurology. 2003;60:927-934
PubMed   |  Link to Article
Watson CP, Moulin D, Watt-Watson J, Gordon A, Eisenhoffer J. Controlled-release oxycodone relieves neuropathic pain: a randomized controlled trial in painful diabetic neuropathy.  Pain. 2003;105:71-78
PubMed   |  Link to Article
Morley JS, Bridson J, Nash TP, Miles JB, White S, Makin MK. Low-dose methadone has an analgesic effect in neuropathic pain: a double-blind randomized controlled crossover trial.  Palliat Med. 2003;17:576-587
PubMed   |  Link to Article
Rowbotham MC, Twilling L, Davies PS, Reisner L, Taylor K, Mohr D. Oral opioid therapy for chronic peripheral and central neuropathic pain.  N Engl J Med. 2003;348:1223-1232
PubMed   |  Link to Article
Maier C, Hildebrandt J, Klinger R, Henrich-Eberl C, Lindena G.MONTAS Study Group.  Morphine responsiveness, efficacy and tolerability in patients with chronic non-tumor associated pain: results of a double-blind placebo-controlled trial (MONTAS).  Pain. 2002;97:223-233
PubMed   |  Link to Article
Kalman S, Osterberg A, Sorensen J, Boivie J, Bertler A. Morphine responsiveness in a group of well-defined multiple sclerosis patients: a study with i.v. morphine.  Eur J Pain. 2002;6:69-80
PubMed   |  Link to Article
Benedetti F, Vighetti S, Amanzio M.  et al.  Dose-response relationship of opioids in nociceptive and neuropathic postoperative pain.  Pain. 1998;74:205-211
PubMed   |  Link to Article
Cook RJ, Sackett DL. The number needed to treat: a clinically useful measure of treatment effect.  BMJ. 1995;310:452-454
PubMed   |  Link to Article
Carr DB, Goudas LC, Balk EM, Bloch R, Ioannidis JP, Lau J. Evidence report on the treatment of pain in cancer patients.  J Natl Cancer Inst Monogr. 2004;32:23-31
PubMed   |  Link to Article
Stanton-Hicks MD, Burton AW, Bruehl SP.  et al.  An updated interdisciplinary clinical pathway for CRPS: report of an expert panel.  Pain Pract. 2002;2:1-16
Link to Article
McNicol E, Strassels S, Goudas L, Lau J, Carr D. Nonsteroidal anti-inflammatory drugs, alone or combined with opioids, for cancer pain: a systematic review.  J Clin Oncol. 2004;22:1975-1992
PubMed   |  Link to Article
Mailis A, Furlan A. Sympathectomy for neuropathic pain.  Cochrane Database Syst Rev. 2003;(2):CD002918
PubMed
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
PubMed   |  Link to Article
Farrar JT, Portenoy RK, Berlin JA, Kinman JL, Strom BL. Defining the clinically important difference in pain outcome measures.  Pain. 2000;88:287-294
PubMed   |  Link to Article
Cepeda MS, Africano JM, Polo R, Alcala R, Carr DB. What decline in pain intensity is meaningful to patients with acute pain?  Pain. 2003;105:151-157
PubMed   |  Link to Article
Farrar JT, Young JP Jr, LaMoreaux L, Werth JL, Poole RM. Clinical importance of changes in chronic pain intensity measured on an 11-point numerical pain rating scale.  Pain. 2001;94:149-158
PubMed   |  Link to Article
Galer BS, Harle J, Rowbotham MC. Response to intravenous lidocaine infusion predicts subsequent response to oral mexiletine: a prospective study.  J Pain Symptom Manage. 1996;12:161-167
PubMed   |  Link to Article
Attal N, Rouaud J, Brasseur L, Chauvin M, Bouhassira D. Systemic lidocaine in pain due to peripheral nerve injury and predictors of response.  Neurology. 2004;62:218-225
PubMed   |  Link to Article
Cohen SP, Chang AS, Larkin T, Mao J. The intravenous ketamine test: a predictive response tool for oral dextromethorphan treatment in neuropathic pain.  Anesth Analg. 2004;99:1753-1759
PubMed   |  Link to Article
McNicol E, Horowicz-Mehler N, Fisk RA.  et al.  Management of opioid side effects in cancer-related and chronic noncancer pain: a systematic review.  J Pain. 2003;4:231-256
PubMed
Sullivan M, Ferrell B. Ethical challenges in the management of chronic nonmalignant pain: negotiating through the cloud of doubt.  J Pain. 2005;6:2-9
PubMed   |  Link to Article
Dunbar SA, Katz NP. Chronic opioid therapy for nonmalignant pain in patients with a history of substance abuse: report of 20 cases.  J Pain Symptom Manage. 1996;11:163-171
PubMed   |  Link to Article
Wittick H, Carr DBPain Management: Evidence, Outcomes and Quality of Life: A Sourcebook. Amsterdam, the Netherlands: Elsevier; 2005

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