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Background Although opioids are commonly used to treat chronic neuropathic pain, there are limited data to guide their use. Few controlled trials have been performed, and many types of neuropathic pain remain unstudied.
Methods Adults with neuropathic pain that was refractory to treatment were randomly assigned to receive either high-strength (0.75-mg) or low-strength (0.15-mg) capsules of the potent µ-opioid agonist levorphanol for eight weeks under double-blind conditions. Intake was titrated by the patient to a maximum of 21 capsules of either strength per day. Outcome measures included the intensity of pain as recorded in a diary, the degree of pain relief, quality of life, psychological and cognitive function, the number of capsules taken daily, and blood levorphanol levels.
Results Among the 81 patients exposed to the study drug, high-strength levorphanol capsules reduced pain by 36 percent, as compared with a 21 percent reduction in pain in the low-strength group (P=0.02). On average, patients in the high-strength group took 11.9 capsules per day (8.9 mg per day) and patients in the low-strength group took close to the 21 allowed (18.3 capsules per day; 2.7 mg per day). Affective distress and interference with functioning were reduced, and sleep was improved, but there were no differences between the high-strength group and the low-strength group in terms of these variables. Noncompletion of the study was primarily due to side effects of the opioid. Patients with central pain after stroke were the least likely to report benefit.
Conclusions The reduction in the intensity of neuropathic pain was significantly greater during treatment with higher doses of opioids than with lower doses. Higher doses produced more side effects without significant additional benefit in terms of other outcome measures.
There are important issues with respect to the design of such trials. First, it is difficult to use a placebo control group, since the patients receiving placebo will have unrelieved chronic pain. In trials in which opioids are active treatments, their side effects can easily reveal the treatment-group assignment to which patients are initially blinded. "Active placebo" agents, such as lorazepam or benztropine, may improve blinding but may produce serious adverse effects, especially in the elderly. Therefore, we took advantage of the dose-dependent nature of opioid analgesia to test efficacy by comparing two different doses under randomized, double-blind conditions in an eight-week study involving patients with neuropathic pain of central or peripheral origin.14 Within preset limits for capsule intake, patients titrated their own doses to attain the optimal balance between pain relief and side effects. The potent µ-opioid agonist levorphanol was chosen for its six-to-eight-hour duration of analgesic action, relatively simple pharmacokinetics, and receptor selectivity.14,15,16,17
Methods
Study Design
Patients were randomly assigned to receive either low-strength (0.15-mg) or high-strength (0.75-mg) levorphanol capsules. As shown in Figure 1, after a one-week period for the collection of base-line data, patients received levorphanol therapy for eight weeks, after which the doses were tapered over a period of one to four weeks. Within the limits of safety and tolerability, patients could titrate their doses up to 21 capsules per day (7 capsules three times a day) by the end of the fourth week of treatment. Maximal allowable doses were therefore 3.15 mg per day in the low-strength group and 15.75 mg per day in the high-strength group. The study was approved by the institutional review board at the University of California, San Francisco, and the California Research Advisory Panel. Written informed consent was obtained from all patients.
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Adults with neuropathic pain due to confirmed peripheral neuropathy or focal nerve injury, postherpetic neuralgia, spinal cord injury with incomplete myelopathy, central pain following a stroke or focal brain lesion, or clinically definite multiple sclerosis were recruited by advertisements and referrals from physicians. Criteria for exclusion included previous opioid therapy exceeding 360 mg of codeine per day or the equivalent; allergy to levorphanol; another pain problem of equal or greater severity; cognitive impairment; ongoing major depression with a risk of suicide; antisocial or borderline personality disorder; unstable health; clinically significant liver, renal, or pulmonary disease; sleep apnea; active treatment for cancer; immunosuppression due to drugs or disease; current drug or alcohol abuse; and history of opioid abuse. Procedures for screening visits included medical history taking, physical examination, evaluation by a psychologist (including neuropsychological testing and the Structured Clinical Interview of the Diagnostic and Statistical Manual of Mental Disorders, fourth edition),18 routine hematologic and chemical analyses, and testing of urine for drugs of abuse.
Outcome Measures
Patients used a daily diary to score their pain daily on a visual-analogue scale labeled "no pain" at 0 mm and "worst pain imaginable" at 100 mm. Each evening, patients rated the average intensity of their pain during the preceding 24 hours.19 Each patient used a categorized pain-relief scale to score the pain relief achieved since beginning study treatment; on this scale, 0 indicated "worse" pain, 1 "no pain relief," 2 "slight" pain relief, 3 "moderate" pain relief, 4 "a lot" of pain relief, and 5 "complete" pain relief.19 In addition, patients completed several other assessments at the beginning of the study and thereafter as noted below. These assessments included the Profile of Mood States, which includes 65 items rated from 0 to 4 and scored in terms of total mood disturbance20; the Multidimensional Pain Inventory, a 61-item inventory entailing 13 empirically derived scales and assessing the effect of pain on quality of life, perceived social support, and ability to engage in daily activities21; the Symbol–Digit Modalities Test, which assesses attention or concentration and immediate recall through verbal matching of meaningless geometric designs with a number key22; and the Opiate-Agonist Effects Scale and Opiate Withdrawal Scale, 16-item and 21-item questionnaires on which patients rate symptoms related to agonist and antagonist activity on a 0-to-4 scale.23
Study Visits and Treatment
After the screening visit, study visits took place at the start of the base-line week; the beginning of the first, second, fourth, sixth, and eighth weeks of treatment; at the initiation of the tapering of the dose of the study drug; in the middle of the tapering period; and at the end of the study (Figure 1). Patients kept a daily diary to record their intake of study capsules, their use of concomitant medications, and their daily pain on the visual-analogue scale described above. Patients were contacted by telephone every 7 to 14 days so that investigators could monitor compliance and safety. After complete discontinuation of previous opioid use (if any) for at least one week, the base-line evaluation took place, including repeated urine testing for opioids. Procedures at subsequent study visits included measurement of vital signs, physical examination, review of the daily diary, counting of levorphanol capsules, and the completion of the assessments described above. Patients began taking the study drug at the visit at the beginning of week 1 if their average daily pain according to the diary scale exceeded 25 mm during the base-line week. They continued to receive all other medical treatments and stable nonopioid therapies for pain, but were not allowed to begin any new treatments for pain.
Randomization was stratified according to sex, age (
70 years or >70 years), and diagnosis (peripheral neuropathy or focal nerve injury, postherpetic neuralgia, central pain following stroke or focal brain lesion, spinal cord injury, or multiple sclerosis). Low-strength capsules and high-strength capsules were identical in appearance and were packaged in patient-specific bottles. Maximal total daily intake was 3 capsules during week 1 of treatment, 9 capsules during week 2, 15 capsules during week 3, and 21 capsules from week 4 through the end of week 8. The minimal dose was one capsule per day. Throughout the study, patients were encouraged to find the optimal balance between pain reduction and side effects within the limits of the protocol. The visit at the beginning of week 8 also included screening of urine for opioids, an interview with a psychologist, and measurement of the blood levorphanol level.24 On completion of eight weeks of treatment or at the time of withdrawal from the study, patients tapered their dose of levorphanol to zero over a period of one to four weeks.
Statistical Analysis
Base-line demographic variables were compared by Fisher's exact test or an unpaired t-test. The primary outcome measure was the change in the weekly averages of the daily ratings of pain on the visual-analogue scale from the base-line week through the eighth week of treatment before the tapering of the dose of the study drug. The primary outcome measure of the mean pain ratings for the two treatment groups was tested with the use of a repeated-measures, mixed-effects model for longitudinal data.25 This procedure allowed the use of all data collected from all patients exposed to the study drug without the exclusion of patients from the analysis or the imputation of missing data. As a secondary analysis, we reestimated the model using the base-line scores on the visual-analogue scale as an additional covariate.
Secondary measures analyzed in the group of all patients exposed to the study drug included the category of pain relief (analyzed by unpaired t-test), maximal weekly capsule intake (by unpaired t-test), and change from base line to the last week of treatment for the Profile of Mood States, Symbol–Digit Modalities Test, Opiate-Agonist Effects Scale, and Opiate Withdrawal Scale (all by analysis of covariance). Results on the Multidimensional Pain Inventory were analyzed (by analysis of covariance) only for patients who completed the study (patients who continued therapy with the study drug through week 8). P values of less than 0.05 were considered to indicate statistical significance. No interim analyses were scheduled or performed.
Results
Study Patients
A total of 100 patients were recruited, but 19 did not undergo randomization and did not receive study medication (14 withdrew consent, 1 had pain scores below the minimal level, and 4 were excluded after the psychological evaluation). Of 81 patients who received levorphanol, the 43 randomly assigned to high-strength capsules and the 38 assigned to low-strength capsules were similar with respect to sex, age, race, cause of pain, average daily pain at base line, and duration of pain (Table 1). Twenty-three patients had pain originating in the central nervous system (central pain following stroke or focal brain lesion, spinal cord injury, or multiple sclerosis), and 58 had pain originating in the peripheral nervous system (peripheral neuropathy, focal nerve injury, or postherpetic neuralgia).
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Primary Outcome Measure
The intensity of pain as judged by the ratings on the visual-analogue scale during the base-line week was moderately severe in both groups (mean [±SD] in the high-strength group, 65.4±18.2 mm; mean in the low-strength group, 69.3±17.0 mm; P=0.33). The degree of reduction of pain was significantly greater in the high-strength group (a 36 percent reduction to 42.1±26.5 mm) than in the low-strength group (a 21 percent reduction to 53.4±24.7 mm, P=0.02) (Figure 2A). The addition of the base-line visual-analogue score as a covariate in statistical models did not alter this result.
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Figure 2B shows the time course of categorized ratings of pain relief. Differences between the treatment groups were greatest at the week 2 visit (P=0.07) but then declined steadily (P=0.31 for the difference at week 8). Among all patients exposed to the study drug in the high-strength group, 47 percent reported pain relief that was moderate or better at the end of treatment. Among those who completed the study taking high-strength capsules, there was a 48 percent reduction in pain, and the proportion reporting pain relief that was moderate or better was 66 percent. Among all patients who completed the study, the ratio of the mean blood levorphanol level in the high-strength group at week 8 (4.8 ng per milliliter) to the mean level in the low-strength group (1.4 ng per milliliter) closely mirrored the ratio of the actual levels of levorphanol intake.
A total of 59 patients completed eight weeks of levorphanol therapy — 67 percent in the high-strength group and 79 percent in the low-strength group (P=0.32). Patients in the high-strength group took significantly fewer capsules each day (11.9±5.5 vs. 18.3±4.3 capsules per day, P<0.001) (Figure 2C). Patients assigned to high-strength capsules took a mean dose of 8.9 mg per day, and patients assigned to low-strength capsules took a mean dose of 2.7 mg per day. As shown in Figure 3, there was a broad range of capsule intake in each group, but there was minimal overlap in actual levorphanol intake, since all but six patients in the high-strength group exceeded 3.15 mg per day.
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No base-line measure significantly predicted which patients would withdraw from the study, but 7 of 10 patients with central pain due to a stroke or focal brain lesion did not complete the study. Reasons for withdrawal from the study included physical or psychological adverse events in 15 patients (12 in the high-strength group and 3 in the low-strength group, P=0.06), treatment failure in 3 patients, lack of adherence to the protocol in 1 patient, and other reasons in 3 patients. According to their self-ratings while they were still taking the study drug, those who later withdrew from the study were less talkative (P=0.001), more restless (P=0.007), and more depressed (P=0.005) than patients who went on to complete the study. At the time of withdrawal from the study, these patients were taking fewer capsules than those who went on to complete the study and had a mean reduction in pain of only 10 percent.
No serious or unexpected drug-related adverse events occurred. One death due to long-standing cardiovascular disease occurred in the low-strength group. Opioid-agonist effects measured on the subscales entitled "Dry Mouth," "Itchy Skin," "Sweating," "Sleepy," "Noise," "Carefree," and "Drunken" increased during treatment in both treatment groups. As compared with patients in the low-strength group, those in the high-strength group reported significantly greater effects with regard to "Itchy Skin," "Sweating," and "Skin Clammy." Some adverse effects were reported only by patients in the high-strength group, including anger, irritability, or mood or personality change in six patients, generalized weakness or confusion in five patients, and dizziness or loss of equilibrium in two patients. One patient had suicidal ideation because of worsening pain during the tapering period, and her primary physician decided to continue levorphanol therapy.
Discussion
This double-blind dose–response study demonstrates that the reduction in neuropathic pain achieved with higher doses of the potent opioid levorphanol (through the use of a higher-strength preparation) was significantly greater than the reduction achieved with lower doses (pain reduction, 36 percent vs. 21 percent). Patients randomly assigned to low-strength levorphanol capsules took close to the maximal number of capsules allowed. However, the mean opioid intake in the low-strength group, 2.7 mg per day, is far from a placebo level. In patients receiving repeated doses, 3 mg of levorphanol is equivalent to as much as 45 to 90 mg of oral morphine or 30 to 45 mg of oral oxycodone — the latter being a dose that has been shown in a placebo-controlled study to relieve postherpetic neuralgia.12
We chose a dose–response design over a placebo-controlled study for several reasons. Opioids are already an approved therapy for pain, and enrolled patients had severe daily pain originating in the central or peripheral nervous system despite having access to nonopioid medications for pain control. The distinctive side effects of opioids make it difficult to maintain blinding with the use of an inactive placebo, and "active" placebos carry their own risks of adverse effects. Without a placebo control group, the reductions in pain cannot be attributed to the effects of the opioids. The significant differences in pain reduction between the study groups and the return to the base-line levels of pain after the discontinuation of opioid treatment strongly suggest that higher-dose opioids effectively reduce the intensity of chronic neuropathic pain. As compared with a placebo-controlled study, a dose–response study is less able to show differences between treatment groups in complex measures that may be less responsive to opioid therapy, such as mood and quality of life. In our study, the advantage of high-strength capsules was limited to improved pain reduction.
High rates of withdrawal from the study, mostly because of side effects, have been reported before in studies of opioids for neuropathic pain. In a placebo-controlled crossover trial of oxycodone for postherpetic neuralgia, 24 percent of patients did not complete the trial.12 Recently, Raja and colleagues compared controlled-release morphine with the tricyclic antidepressant nortriptyline and a placebo in patients with postherpetic neuralgia.13 Although pain reduction with morphine was superior to that with placebo, and there was a trend toward superiority to that with nortriptyline, patients in that study were much more likely to withdraw during the opioid-therapy phase. In our study, patients were encouraged to find the optimal balance between pain reduction and adverse effects and could remain in the study by taking as little as one capsule per day. A long titration period and a strict upper limit for capsule intake were used to protect the patients, many of whom were elderly or partially disabled or had not previously taken opioids. Despite these measures, 27 percent of patients withdrew. Furthermore, anger, irritability, and personality changes were reported only by patients in the high-strength group, and more patients in this group withdrew from the study. On the basis of our findings, it is clear that not all patients will benefit from opioids, and some will have worsening of mood and function without relief of pain.
The belief that tolerance to opioid analgesics quickly eliminates any initial analgesic benefit remains widespread.26,27,28 Retrospective and open-label prospective studies have not adequately addressed the important issue of tolerance.29,30,31,32,33 Moulin and colleagues compared controlled-release morphine with placebo in 61 patients with musculoskeletal pain.34 Pain reduction of about 25 percent occurred during the initial three-week titration period but was largely lost during the subsequent six-week period of administration of stable doses. In our study, daily capsule intake and ratings of intensity of pain were stable during the last two weeks of therapy, suggesting that there was no tolerance in the form of a loss of analgesic efficacy that might be reflected in a rapid escalation of doses. There was no addictive behavior observed. In fact, only four patients in the high-strength group ever reached the maximal capsule intake allowed. However, prospective, controlled studies assessing the stability of pain control and dose requirements over periods of many months to years are needed.
The magnitude of the reduction in neuropathic pain achieved with high-strength levorphanol capsules is similar to that reported in placebo-controlled studies of tricyclic antidepressants and the anticonvulsant gabapentin. A placebo-controlled trial of eight weeks of treatment with gabapentin in 229 patients with postherpetic neuralgia reported a 33 percent reduction in the intensity of pain and moderate or better pain relief in 50 percent of patients.35 In our study, which included patients with central pain, the intensity of pain decreased by 36 percent during therapy with high-strength levorphanol, and moderate or better pain relief was achieved in 47 percent of patients. Our results showing a 48 percent reduction in pain and moderate or better pain relief in 66 percent of patients in the high-strength group who completed the study are almost identical to results reported in four controlled trials of tricyclic antidepressants for peripheral neuropathy and postherpetic neuralgia in which only the data from patients who completed the study were analyzed.18,36,37,38 In summary, higher doses of the opioid levorphanol are more effective than low doses in reducing the intensity of chronic neuropathic pain originating in the central or peripheral nervous system, but in many patients, pain relief is not achieved or there are intolerable side effects.
Supported by the National Institute on Drug Abuse (project DA-01696) and the National Institute of Neurological Disorders and Stroke (Pain Research Training grant NS07625, grant K24-NS02164, and project NS21445).
Dr. Rowbotham reports having received fees for consulting from Allergan, Biogen, Grunenthal, King Pharmaceuticals–Lineberry Research, Ortho–McNeil–Johnson & Johnson, Pfizer, Schwarz BioSciences, and WinPharm; lecturing on behalf of Pfizer and Novartis; having received grant support from UCB Pharma, Johnson & Johnson, Endo Pharmaceuticals, and Pfizer; and having received royalties from Hind Health Care for a topical local anesthetic patch. Ms. Davies reports having received consulting fees from Endo Pharmaceuticals. Dr. Taylor reports owning stock in Pfizer. Dr. Mohr reports having received grant support from Biogen.
We are indebted to Erika Friedman, Christina Verkempinck, R.N., Barth Wilsey, M.D., Bokgi Choi, M.D., Robert Cluff, M.D., Karin Petersen, M.D., Reese Jones, M.D., Tom Everhart, Ph.D., Kaye Welch, and Kevin Delucchi, Ph.D., for their valuable contributions.
Source Information
From the Pain Clinical Research Center, Department of Neurology (M.C.R., L.T., P.S.D., L.R., K.T., D.M.), and the Department of Anesthesia (M.C.R.), University of California, San Francisco, School of Medicine; and the University of California, San Francisco, School of Pharmacy (L.R.) — all in San Francisco.
Address reprint requests to Dr. Rowbotham at the Pain Clinical Research Center, 1701 Divisadero St., Ste. 480, San Francisco, CA 94115.
References
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Related Letters:
Chronic Neuropathic Pain
Canavero S., Bonicalzi V., Simpson J. K. III, Foley K. M.
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N Engl J Med 2003;
348:2688-2689, Jun 26, 2003.
Correspondence
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