Dongsheng Tu

Nortriptyline and gabapentin, alone and in combination for neuropathic pain: a double-blind, randomised controlled crossover trial

BACKGROUNDnDrugs for neuropathic pain have incomplete efficacy and dose-limiting side-effects when given as monotherapy. We assessed the efficacy and tolerability of combined nortriptyline and gabapentin compared with each drug given alone.nnnMETHODSnIn this double-blind, double-dummy, crossover trial, patients with diabetic polyneuropathy or postherpetic neuralgia, and who had a daily pain score of at least 4 (scale 0-10), were enrolled and treated at one study site in Canada between Nov 5, 2004, and Dec 13, 2007. 56 patients were randomised in a 1:1:1 ratio with a balanced Latin square design to receive one of three sequences of daily oral gabapentin, nortriptyline, and their combination. In sequence, a different drug was given to each randomised group in three treatment periods. During each 6-week treatment period, drug doses were titrated towards maximum tolerated dose. The primary outcome was mean daily pain at maximum tolerated dose. Analysis was by intention to treat. This trial is registered, number ISRCTN73178636.nnnFINDINGSn45 patients completed all three treatment periods; 47 patients completed at least two treatment periods and were analysed for the primary outcome. Mean daily pain (0-10; numerical rating scale) was 5.4 (95% CI 5.0 to 5.8) at baseline, and at maximum tolerated dose, pain was 3.2 (2.5 to 3.8) for gabapentin, 2.9 (2.4 to 3.4) for nortriptyline, and 2.3 (1.8 to 2.8) for combination treatment. Pain with combination treatment was significantly lower than with gabapentin (-0.9, 95% CI -1.4 to -0.3, p=0.001) or nortriptyline alone (-0.6, 95% CI -1.1 to -0.1, p=0.02). At maximum tolerated dose, the most common adverse event was dry mouth, which was significantly less frequent in patients on gabapentin than on nortriptyline (p<0.0001) or combination treatment (p<0.0001). No serious adverse events were recorded for any patients during the trial.nnnINTERPRETATIONnCombined gabapentin and nortriptyline seems to be more efficacious than either drug given alone for neuropathic pain, therefore we recommend use of this combination in patients who show a partial response to either drug given alone and seek additional pain relief. Future trials should compare other combinations to their respective monotherapies for treatment of such pain.nnnFUNDINGnCanadian Institutes of Health Research.

A placebo-controlled randomized clinical trial of perioperative administration of gabapentin, rofecoxib and their combination for spontaneous and movement-evoked pain after abdominal hysterectomy

&NA; Current treatments for post‐injury movement‐evoked pain are inadequate. Non‐opioids may complement opioids, which preferentially reduce spontaneous pain, but most have incomplete efficacy as single agents. This trial evaluates efficacy of a gabapentin–rofecoxib combination following hysterectomy. In addition to IV‐PCA morphine, 110 patients received either placebo, gabapentin (1800 mg/day), rofecoxib (50 mg/day) or a gabapentin–rofecoxib combination (1800/50 mg/day) starting 1 h pre‐operatively for 72 h. Outcomes included pain at rest, evoked by sitting, peak expiration and cough, morphine consumption and peak expiratory flow (PEF). For placebo, gabapentin, rofecoxib and combination, 24 h pain (100 mm VAS) was: at rest—23.6 (P<0.05 vs. all treatments), 13.8, 14.4 and 12.1; during cough—50.7 (P<0.05 vs. all treatments), 41.5, 44.8 and 30.8; 48 h morphine consumption (mg) was: 130.4 (P<0.05 vs. all treatments), 81.7, 75.6 and 57.2 (P<0.05 vs. gabapentin and rofecoxib) and 48 h PEF (% baseline) was: 63.9 (P<0.05 vs. all treatments), 77.2, 76.7 and 87.5 (P<0.05 vs. gabapentin and rofecoxib). Adverse effects were similar in all groups except sedation which was more frequent with gabapentin. Combination and rofecoxib reduced pain interference with movement, mood and sleep (P<0.05) and combination was superior to gabapentin for all these three (P<0.05). These data suggest that a gabapentin–rofecoxib combination is superior to either single agent for postoperative pain. Other benefits include opioid sparing, reduced interference with movement, mood and sleep and increased PEF suggesting accelerated pulmonary recovery. Future research should identify optimal dose‐ratios for this and other analgesic combinations.

A randomized, double-blind, controlled trial of perioperative administration of gabapentin, meloxicam and their combination for spontaneous and movement-evoked pain after ambulatory laparoscopic cholecystectomy.

BACKGROUND: Hysterectomy and spinal surgery inpatient trials suggest favorable interactions between cyclooxgenase-2 inhibitors and gabapentin/pregabalin on postoperative days 1–2. We present the first trial of meloxicam-gabapentin combination after outpatient laparoscopic cholecystectomy. METHODS: This was a randomized, double-blind trial comparing daily oral administration of 1) meloxicam 15 mg, 2) gabapentin 1200–1600 mg, and 3) a combination of the two starting 1 h before until 2 days after surgery. Primary outcomes included day of surgery spontaneous and movement-evoked pain. Secondary outcomes included pain on Days 1, 2, and 30, adverse effects, opioid consumption, spirometry, pain-related interference, hospital discharge time, return to work time, and patient satisfaction. RESULTS: On the day of surgery, 60-min rest pain (0–10 numerical rating scale ± sd) was significantly lower (P < 0.05) with gabapentin alone (2.0 ± 1.6) versus meloxicam alone (3.6 ± 2.1). Observed pain differences between the combination (2.9 ± 2.1) and gabapentin alone were fairly small in favor of gabapentin alone (P > 0.05). Secondary analyses indicated that nausea was significantly less frequent with the combination (24%) versus the single-drug meloxicam (57%) only. CONCLUSION: Although nausea was reduced with combination therapy, this trial provides little or no support for the combined use of meloxicam and gabapentin for pain relief on the day of surgery. This suggests that perioperative analgesic polypharmacy may not always be necessary or appropriate.

Combination of morphine with nortriptyline for neuropathic pain.

Abstract First-line neuropathic pain drugs, including tricyclic antidepressants, are not always effective, and opioids have been recommended as second line. This trial evaluates a nortriptyline–morphine combination, compared with each monotherapy. In this randomized, double-blind crossover trial, patients with neuropathic pain were enrolled at 1 site between January 25, 2010, and May 22, 2014, and randomized in a 1:1:1 ratio using a balanced Latin square design to receive oral nortriptyline, morphine, and their combination. During each of three 6-week periods, doses were titrated toward maximal tolerated dose (MTD). The primary outcome was average daily pain at MTD, and secondary outcomes included other pain, mood and quality of life measures, and adverse effects. Sixty-two patients were screened, 52 enrolled, and 39 completed at least 2 treatment periods. Average daily pain (0-10) at baseline was 5.3 and at MTD was 2.6 for combination vs 3.1 for nortriptyline (P = 0.046) and 3.4 for morphine (P = 0.002). Brief Pain Inventory scores for average and present pain were also significantly lower for combination vs each monotherapy. Combination treatment resulted in moderate–severe constipation in 43% vs 46% with morphine (P = 0.82) and 5% with nortriptyline (P < 0.0001). Combination treatment resulted in moderate–severe dry mouth in 58% vs 49% with nortriptyline (P = 0.84) and 13% with morphine (P < 0.0001). This trial suggests superior efficacy of a nortriptyline–morphine combination over either monotherapy with constipation, dry mouth, and somnolence as the most frequent adverse effects.

Combination of pregabalin with duloxetine for fibromyalgia: a randomized controlled trial.

Abstract Fibromyalgia is a syndrome characterized by chronic widespread pain and associated with sleep disturbance, depression, fatigue, and cognitive dysfunction. Polypharmacy is commonly used, but supportive evidence is limited. Most fibromyalgia trials focus primarily on pain reduction with monotherapy. This trial compares a pregabalin–duloxetine combination to each monotherapy. Using a randomized, double-blind, 4-period crossover design, participants received maximally tolerated doses of placebo, pregabalin, duloxetine, and pregabalin–duloxetine combination—for 6 weeks. Primary outcome was daily pain (0-10); secondary outcomes included global pain relief, Fibromyalgia Impact Questionnaire, SF-36 survey, Medical Outcomes Study Sleep Scale, Beck Depression Inventory (BDI-II), adverse events, and other measures. Of 41 participants randomized, 39 completed ≥2 treatments. Daily pain during placebo, pregabalin, duloxetine, and combination was 5.1, 5.0, 4.1, and 3.7, respectively (P < 0.05 only for combination vs placebo, and pregabalin). Participants (%) reporting ≥moderate global pain relief were 18%, 39%, 42%, and 68%, respectively (P < 0.05 for combination vs placebo, pregabalin, and duloxetine). Fibromyalgia Impact Questionnaire scores were 42.9, 37.4, 36.0, and 29.8, respectively (P < 0.05 for combination vs placebo, pregabalin, and duloxetine). SF-36 scores were 50.2, 55.7, 56.0, and 61.2, respectively (P < 0.05 for combination vs placebo, pregabalin, and duloxetine). Medical Outcomes Study Sleep Scale scores were 48.9, 35.2, 46.1, and 32.1, respectively (P < 0.05 only for combination vs placebo, and duloxetine). BDI-II scores were 11.9, 9.9, 10.7, and 8.9, respectively (P < 0.05 only for combination vs placebo). Moderate–severe drowsiness was more frequent during combination vs placebo. Combining pregabalin and duloxetine for fibromyalgia improves multiple clinical outcomes vs monotherapy. Continued research should compare this and other combinations to monotherapy for fibromyalgia.

Sensory and affective pain descriptors respond differentially to pharmacological interventions in neuropathic conditions.

Objectives:Pain management is limited by inability to match a patient’s condition—and pain mechanisms—to optimal treatment(s). Much is known about pain treatment from animal investigations, but antinociceptive mechanisms cannot be readily explored in clinical studies. Evidence suggests that self-report verbal pain descriptors characterize important pain dimensions and may reflect diverse underlying mechanisms. Methods:This exploratory analysis of data from a trial of a gabapentin-morphine combination evaluated effects of treatment on short-form McGill Pain Questionnaire sensory and affective descriptor profiles and prediction of treatment response by these descriptors. Results:Severity of “throbbing,” “shooting,” and “aching” improved preferentially with morphine over gabapentin, whereas “tiring-exhausting” and “sickening” improved preferentially with gabapentin over morphine. Improvement in descriptor severity with gabapentin-morphine combination was superior to active placebo for 12 of 15 short-form McGill Pain Questionnaire descriptors, whereas morphine and gabapentin were superior to active placebo for only 7 and 6 descriptors, respectively. Baseline moderate-severe “throbbing” and “hot-burning” predicted poor outcomes with gabapentin, whereas moderate-severe “aching” and “punishing-cruel” predicted favorable outcomes with gabapentin. Baseline “throbbing” severity also predicted poor outcomes with morphine. Baseline allodynia predicted superior reduction of “stabbing” with morphine but not with gabapentin alone. Discussion:These results point to the hypothesis that sensory and affective pain descriptor profiles exhibit a treatment-specific response. Larger, more definitive, investigations to evaluate treatment-specific effects on multiple sensory and affective pain descriptors, and prediction of treatment response by these descriptors, will advance efforts toward developing and implementing more effective individualized pain therapies.

The effect of triple vs. double nonopioid therapy on postoperative pain and functional outcome after abdominal hysterectomy: a randomised double-blind control trial.

BACKGROUND Movement-evoked pain is more severe than pain at rest and is likely to interfere more with functional recovery after surgery. OBJECTIVE To compare triple vs. double nonopioid perioperative analgesic regimens in women undergoing abdominal hysterectomy. DESIGN A randomised, parallel design, double-blind controlled trial. SETTING A single-centre trial. Study period from November 2009 to July 2013. PATIENTS Adults (>18 years) of American Society of Anesthesiologists’ status 1 to 2 scheduled for abdominal hysterectomy. INTERVENTIONS Patients were randomised to one of four study treatment groups: acetaminophen, meloxicam and gabapentin (AMG); acetaminophen and meloxicam; acetaminophen and gabapentin; and meloxicam and gabapentin. In addition to intravenous patient-controlled opioid analgesia, study treatments were administered for 48u200ah, starting 1u200ah preoperatively. MAIN OUTCOME MEASURES The primary outcome was cough-evoked pain. Secondary outcomes included pain at rest, during sitting and peak expiration, opioid consumption, side effects, peak expiratory flow rate, timed up and go test (TUG), and modified Brief Pain Inventory (mBPI). RESULTS Interim analysis indicated a minimal chance of demonstrating superiority of the triple regimen group over all three double regimen groups if the trial were to be recruited to planned sample size. Thus, the trial was prematurely terminated for futility. All four analgesic regimens were well tolerated. Exploratory analyses revealed consistent significant negative correlations between pain and TUG and between pain and interference with activity, walking and sleep. CONCLUSION This trial failed to demonstrate substantial benefits with the addition of a third nonopioid analgesic to three different double-drug regimens. Further research is needed that will more definitively support expanding multimodal analgesic practices. Our results demonstrate consistent correlations between evoked pain and functional outcomes further emphasising the need for improved analgesic regimens that will accelerate postsurgical functional recovery. TRIAL REGISTRATION International Standard Randomised Controlled Trial Number Register 12723675.

Response to comment by Dahl and Kehlet

We appreciate the keen interest of Drs Dahl and Kehlet in our placebo-controlled randomized clinical trial of perioperative administration of gabapentin, rofecoxib and their combination for spontaneous and movement-evoked pain after abdominal hysterectomy. Indeed, preliminary results presented in poster form at the 2003 American Pain Society Annual Meeting were from the interim analysis of this trial conducted upon completion of 76 patients. The objective of this interim analysis was to determine whether the results were extreme enough (both positive and negative) to warrant early stopping of the study. No individual patients were unblinded during the interim analysis. The decision on early stopping was implicitly guided by the Lan-DeMets alpha spending function with the O’Brien–Fleming boundary (Piantadosi, 1997) which controls the overall type I error of the whole study at the 0.05 level. This stopping rule requires a very small P-value value for early stopping but, if the study is not stopped early (as was the case here), the conventional 0.05 significance level is used for the final analysis including all trial patients.