A randomised, double blind, placebo controlled crossover study of the cholecystokinin 2 antagonist L-365,260 as an adjunct to strong opioids in chronic human neuropathic pain. Topical application of doxepin hydrochloride, capsaicin and a combination of both produces analgesia in chronic human neuropathic pain: a randomized, double-blind, placebo-controlled study. Morphine, gabapentin, or their combination for neuropathic pain. Amitriptyline in neuropathic cancer pain in patients on morphine therapy: a randomized placebo-controlled, double-blind crossover study. Nortriptyline-fluphenazine vs. carbamazepine in the symptomatic treatment of diabetic neuropathy. Combination of alpha lipoic acid and gabapentin, its efficacy in the treatment of Burning Mouth Syndrome: a randomized, double-blind, placebo controlled trial. Amitriptyline and fluphenazine in the treatment of postherpetic neuralgia. Multi-day low dose ketamine infusion as adjuvant to oral gabapentin in spinal cord injury related chronic pain: a prospective, randomized, double blind trial. Morphine, nortriptyline and their combination vs. placebo in patients with chronic lumbar root pain. A pilot study examining topical amitriptyline, ketamine, and a combination of both in the treatment of neuropathic pain. Gabapentin for neuropathic cancer pain: a randomized controlled trial from the Gabapentin Cancer Pain Study Group. Chronic phantom limb pain: the effects of calcitonin, ketamine, and their combination on pain and sensory thresholds. Nortriptyline and fluphenazine in the symptomatic treatment of diabetic neuropathy. A double-blind cross-over study. Management of diabetic neuropathy by sodium valproate and glyceryl trinitrate spray: a prospective double-blind randomized placebo-controlled study. Topical 2% amitriptyline and 1% ketamine in neuropathic pain syndromes: a randomized, double-blind, placebo-controlled trial. Prolonged-release oxycodone enhances the effects of existing gabapentin therapy in painful diabetic neuropathy patients. A double-blind, placebo-controlled trial of a topical treatment for chemotherapy-induced peripheral neuropathy: NCCTG trial N06CA. Nortriptyline and gabapentin, alone and in combination for neuropathic pain: a double-blind, randomised controlled crossover trial. A randomized, controlled trial of oxycodone versus placebo in patients with postherpetic neuralgia and painful diabetic neuropathy treated with pregabalin.
The aim of this study was to establish if the cholecystokinin (CCK) 2 antagonist L-365,260 augments the analgesic effect of morphine in human subjects with chronic neuropathic pain. This is a randomised, double blind, placebo controlled study of 40 adult subjects taking morphine for neuropathic pain. Each received placebo, L-365,260 30 mg and L-365,260 120 mg in three divided doses daily separated by a washout period in random order. Pain, activity, sedation, sleep and side effects were recorded along with 12 lead ECGs, renal and liver function tests and full blood pictures. L-365,260 failed to augment the analgesic effect of morphine at any of the dose levels used. Side effects were minor. There were no changes in ECGs and biochemical indices were unaltered with its use. The CCK 2 antagonist L-365,260 does not augment the analgesic effect of morphine in subjects with chronic neuropathic pain. L-365,260 was well tolerated and side effects from its use were minor. To assess the analgesic efficacy of topical administration of 3.3% doxepin hydrochloride, 0.025% capsaicin and a combination of 3. 3% doxepin and 0.025% capsaicin in human chronic neuropathic pain.
                A randomized, double-blind, placebo-controlled study of 200 consenting adult patients. Patients applied placebo, doxepin, capsaicin or doxepin/capsaicin cream daily for 4 weeks. Patients recorded on a daily basis overall pain, shooting, burning, paraesthesia and numbness using a 0-10 visual analogue scale during the week prior to cream application (baseline levels) and for the 4 week study period. Side-effects and desire to continue treatment were also recorded.
                Overall pain was significantly reduced by doxepin, capsaicin and doxepin/capsaicin to a similar extent. The analgesia with doxepin/capsaicin was of more rapid onset. Capsaicin significantly reduced sensitivity and shooting pain. Burning pain was increased by doxepin and by capsaicin and to a lesser extent by doxepin/capsaicin. Side-effects were minor. One patient requested to continue placebo cream, 17 doxepin cream, 13 capsaicin and 9 the combination of doxepin and capsaicin.
                Topical application of 3.3% doxepin, 0.025% capsaicin and 3.3% doxepin/0. 025% capsaicin produces analgesia of similar magnitude. The combination produces more rapid analgesia. The available drugs to treat neuropathic pain have incomplete efficacy and dose-limiting adverse effects. We compared the efficacy of a combination of gabapentin and morphine with that of each as a single agent in patients with painful diabetic neuropathy or postherpetic neuralgia.
                In this randomized, double-blind, active placebo-controlled, four-period crossover trial, patients received daily active placebo (lorazepam), sustained-release morphine, gabapentin, and a combination of gabapentin and morphine--each given orally for five weeks. The primary outcome measure was mean daily pain intensity in patients receiving a maximal tolerated dose; secondary outcomes included pain (rated according to the Short-Form McGill Pain Questionnaire), adverse effects, maximal tolerated doses, mood, and quality of life.
                Of 57 patients who underwent randomization (35 with diabetic neuropathy and 22 with postherpetic neuralgia), 41 completed the trial. Mean daily pain (on a scale from 0 to 10, with higher numbers indicating more severe pain) at a maximal tolerated dose of the study drug was as follows: 5.72 at baseline, 4.49 with placebo, 4.15 with gabapentin, 3.70 with morphine, and 3.06 with the gabapentin-morphine combination (P<0.05 for the combination vs. placebo, gabapentin, and morphine). Total scores on the Short-Form McGill Pain Questionnaire (on a scale from 0 to 45, with higher numbers indicating more severe pain) at a maximal tolerated dose were 14.4 with placebo, 10.7 with gabapentin, 10.7 with morphine, and 7.5 with the gabapentin-morphine combination (P<0.05 for the combination vs. placebo, gabapentin, and morphine). The maximal tolerated doses of morphine and gabapentin were lower (P<0.05) with the combination than for each drug as single agent. At the maximal tolerated dose, the gabapentin-morphine combination resulted in a higher frequency of constipation than gabapentin alone (P<0.05) and a higher frequency of dry mouth than morphine alone (P<0.05).
                Gabapentin and morphine combined achieved better analgesia at lower doses of each drug than either as a single agent, with constipation, sedation, and dry mouth as the most frequent adverse effects.
                Copyright 2005 Massachusetts Medical Society. Amitriptyline is the most common analgesic adjuvant used in cancer patients with neuropathic pain, even though no specific studies have demonstrated a benefit. A randomized placebo-controlled, double-blind crossover study was designed to evidence the effects of amitriptyline in patients with neuropathic cancer pain.
                Sixteen advanced cancer patients with neuropathic pain on systemic morphine therapy, no longer receiving oncologic treatment, presenting moderate pain (about 4 or more, but less than 7, on a numerical scale of 0-10) in the last week, and given a stable morphine dose in the last 2 days were admitted to the study. During the first week of study, patients were administered 25 mg of amitriptyline or equivalent drops of placebo at night for 3 days and 50 mg for the following 4 days. Doses for patients aged more than 65 years were 15 mg (first 3 days) and 30 mg (3 days after). After a week, a crossover took place for the second week, with the other treatment at an inverse sequence. Opioid consumption, pain intensity, symptoms and adverse effects, mood, sleep, patient's preference, quality of life before starting the study, the first week after and the second week after were recorded.
                No significant benefits in analgesia were found in the global pain intensity of the previous week of treatment, the least pain intensity or the pain evaluated just after a week of treatment, at the moment of the visit, when amitriptyline was compared with placebo. A significant difference was evidenced for the worst pain (P < 0.035). No differences in opioid doses during the period of study were found. Drowsiness, confusion and dry mouth were significantly more intense with amitriptyline than with placebo (P < 0.036, 0.003, and 0.034, respectively). There were no substantial differences between the two treatments in Spitzer's quality of life score and for each item. No differences in patients' preference for the two treatment periods were found. The analgesic effects of amitriptyline were slight and associated with adverse effects.
                In light of the results obtained in the study, the extensive use of the drug for cancer pain should be questioned. We compared the efficacy and tolerance of the combination of nortriptyline-fluphenazine (NF) vs. carbamazepine (CMZ) in the symptomatic therapy of patients with severe, distal, symmetrical, predominantly sensitive diabetic polyneuropathy (DPN). We followed a double blind, crossover, randomized and double placebo design. Sixteen patients with severe DPN participated in the study. Patients received either NF (1 tablet three times a day (tid)), for 2 weeks and 2 tablets tid for the next 2 weeks or CMZ 1/2 tablet tid for 2 weeks and 1 tablet tid for the next 2 weeks. After this, patients received placebos of both drugs (wash-out period), until symptoms returned to baseline levels (100%), then they were crossed over to receive the other comparing drug schedule. A visual analogue scale was used to evaluate the percent changes in pain and paresthesia. HbA1, fasting serum glucose, and safety tests were performed at 2- and 4-week intervals, respectively. Both therapies produced significant improvement of both pain and paresthesia. No statistically significant differences were observed between both therapies for either pain or paresthesia. No significant biochemical changes were observed with any of the two therapies. Side effects were mild and more frequent in the NF period. In this study no superiority of either drug schedule was demonstrated; therefore, the decision to use any of them should be made according to the associated pathology and potential side effects of each drug. Burning Mouth Syndrome (BMS) is a disease that manifests as burning in the tongue or in any area of the oral mucosa, in the absence of clinically verifiable injuries.
                To verify the efficacy of alpha lipoic acid (ALA) and gabapentin (GABA), used individually and jointly, to reduce the burning in patients with burning mouth and establish a drug therapy for the BMS.
                During April and May 2008, we conducted a randomized, double-blind, placebo-controlled trial in the Department of Clinical Stomatology, Faculty of Dentistry, Rosario, Argentina. The gathering of patients was between those ones with BMS who were treated in our service between March 2003 and March 2008 without complying with the applied treatments. The 120 patients were randomly divided into 4 groups and were provided, by lot and in a blinded fashion, with four different treatment cycles consisting of the following drugs: Group A (n = 20) 600 mg / day of alpha lipoic acid for two months, Group B (n = 20) 300 mg / day of gabapentin for two months, Group C (n = 20) a combination of both drugs for two months and Group D (n = 60) 100 mg / day of cellulose starch for two months (control group).
                all 120 patients completed the treatment. The best response was obtained with the combination of ALA + GABA, with a 70% of the cases with reduced burning in this group and a 13.2 times greater chance of presenting positive changes for these patients than those taking placebo. The combined use of drugs that act at different levels of the nociceptive system can be useful for the treatment of this syndrome. Postherpetic neuralgia (PHN) is a vexing problem occurring in 10 to 20 percent of people with from herpes zoster (shingles). Anecdotal reports show that fluphenazine enhances the effects of amitriptyline for the treatment of PHN. The aim of this study was to determine, in a controlled manner, whether this was the case.
                In a double-blind placebo-controlled study, 49 patients with PHN were randomly assigned to four treatment groups: Group 1, amitriptyline; Group 2, amitriptyline and fluphenazine; Group 3, fluphenazine; Group 4, a placebo. An active placebo was used to mimic the anticholinergic side effects of dry mouth. The study lasted 8 weeks, with weekly progress evaluations with use of visual analog scales (VAS), the McGill Pain Questionnaire (MPQ), and a side-effects scale.
                A statistically significant decrease was seen in pain in Groups 1 and 2, and no significant changes were seen in Groups 3 and 4. There was no significant difference when fluphenazine was added to amitriptyline.
                These data support the effectiveness of amitriptyline in treatment of PHN, but do not support the addition of fluphenazine. Severe, intractable, chronic pain is a significant management problem for those involved in the long-term care of spinal cord injury (SCI) patients . Gabapentin, an anticonvulsant, is widely used for treating chronic pain. Ketamine, an NMDA receptor antagonist, has been available in clinical practice for 35 years. Its usefulness in pathological pain states is known. Despite this, no formal research on its effectiveness in treating neuropathic SCI pain exists.
                This double-blind study sought to determine the safety and efficacy of adding a multi-day low dose ketamine infusion to oral gabapentin for treating chronic pain related to post spinal cord injury.
                Randomized, controlled, double blind trial.
                Hospital, in-patient setting.
                Forty patients diagnosed with neuropathic pain secondary to spinal cord injury were randomized into 2 equal groups. Group I received an 80 mg intravenous ketamine infusion diluted in 500 cc normal saline over a 5 hour period daily for one week and 300 mg of gabapentin 3 times daily. Group II received a placebo infusion and 300 mg of gabapentin 3 times daily (continued) after 300 mg of gabapentin 3 times daily. Using the visual analogue scale, pain was assessed prior to treatment, daily following ketamine or placebo infusions for 7 days, and then weekly for one month after infusion termination. Side effects, specifically those related to ketamine or gabapentin, were reported.
                Both groups demonstrated significantly reduced pain scores compared with pre-treatment values (P < 0.05). Group I showed significant pain score improvements over Group II at all measurements (P < 0.0001) during infusion and 2 weeks after infusion termination. There was no statistical difference between the groups at 3 weeks and 4 weeks after infusion termination (P = 0.54 and P = 0.25 respectively). Both drugs were tolerated by all patients; no side effects required intervention.
                Multi-day low dose ketamine infusion as adjuvant to gabapentin in post-spinal cord injury related chronic pain is safe and efficacious in reducing pain, but the effect compared to placebo ceased 2 weeks after infusion termination.
                Study size limited to 40 patients. Although lumbar radicular pain is the most common chronic neuropathic pain syndrome, there have been few randomized studies of drug treatments. We compared the efficacy of morphine (15-90 mg), nortriptyline (25-100 mg), their combination, and a benztropine "active placebo" (0.25-1 mg) in patients with chronic sciatica. Each period consisted of 5 weeks of dose escalation, 2 weeks of maintenance at the highest tolerated doses, and 2 weeks of dose tapering. The primary outcome was the mean daily leg pain score on a 0-10 scale during the maintenance period. Secondary outcomes included a 6-point ordinal global pain relief scale, the Beck Depression Inventory (BDI), the Oswestry Back Pain Disability Index (ODI) and the SF-36. In the 28 out of 61 patients who completed the study, none of the treatments produced significant reductions in average leg pain or other leg or back pain scores. Pain reduction, relative to placebo treatment was, 14% for nortriptyline (95% CI=[-2%, 30%]), 7% for morphine (95% CI=[-8%, 22%]), and 7% for the combination treatment (95% CI=[-4%, 18%]). Mean doses were: nortriptyline alone, 84+/-24.44 (SD) mg/day; morphine alone, 62+/-29 mg/day; and combination, morphine, 49+/-27 mg/day plus nortriptyline, 55 mg+/-33.18 mg/day. Over half of the study completers reported some adverse effect with morphine, nortriptyline or their combination. Within the limitations of the modest sample size and high dropout rate, these results suggest that nortriptyline, morphine and their combination may have limited effectiveness in the treatment of chronic sciatica. The involvement of ongoing peripheral activity in the generation of nociceptive input in neuropathic pain suggests that topical drug delivery may be useful as a treatment strategy. This is a pilot study providing initial information regarding the use of novel topical preparations containing amitriptyline (AMI), ketamine (KET), and a combination of both in the treatment of neuropathic pain.
                The study design included a 2 day randomized, double blind, placebo controlled, 4 way cross-over trial of all treatments, followed by an open label treatment phase using the combination cream for 7 days. Twenty volunteers with chronic neuropathic pain were randomly assigned to treatment order and applied 5 mls of each topical treatment (1% AMI, 0.5% KET, combination AMI 1%/KET 0.5%, and placebo) for 2 days. Measures of pain at the end of each block included the short form McGill Pain Questionnaire (MPQ) and visual analog scales (VAS) for present pain intensity and pain relief. Eleven subjects who judged subjective improvement from any treatment in the initial trial entered the open-label trial and used the combination cream for 7 days. Pain levels were recorded daily using the same measures. Blood levels for amitriptyline and ketamine were performed at 7 days to determine whether systemic absorption had occurred.
                There was no statistically significant difference from placebo after 2 days for any treatment during the double blind component of the trial. In the 11 subjects who used the combination cream, there was a statistically significant effect, with subjects reporting significantly greater analgesia by days 3 to 7 according to measures of pain and pain relief. Blood levels revealed that there was no significant systemic absorption of amitriptyline or ketamine. Only 2 subjects experienced side effects; these were minor and did not lead to discontinuation of the cream.
                This pilot study demonstrated a lack of effect for all treatments in the 2 day double blind placebo controlled trial, followed by analgesia in an open label trial in a subgroup of subjects who chose to use the combination cream for 7 days. Blood analysis revealed no significant systemic absorption of either agent after 7 days of treatment, and creams were well tolerated. A larger scale randomized trial over a longer interval is warranted to examine further effects observed in the open label trial. To determine the analgesic effect of the addition of gabapentin to opioids in the management of neuropathic cancer pain.
                One hundred twenty-one consecutive patients with neuropathic pain due to cancer, partially controlled with systemic opioids, participated in a multicenter, randomized, double-blind, placebo-controlled, parallel-design, 10-day trial from August 1999 to May 2002. Gabapentin was titrated from 600 mg/d to 1,800 mg/d in addition to stable opioid dose. Extra opioid doses were available as needed. Zero to 10 numerical scale was used to rate average daily pain. The average pain score over the whole follow-up period was used as main outcome measure. Secondary outcome measures were: intensity of burning pain, shooting/lancinating pain, dysesthesias (also scored on 0 to 10 numerical scale), number of daily episodes of lancinating pain, presence of allodynia, and daily extra doses of opioid analgesics.
                Overall, 79 patients received gabapentin and 58 (73%) completed the study; 41 patients received placebo and 31 (76%) completed the study. Analysis of covariance (ANCOVA) on the intent-to-treat population showed a significant difference of average pain intensity between gabapentin (pain score, 4.6) and placebo group (pain score, 5.4; P =.0250). Among secondary outcome measures, dysesthesia score showed a statistically significant difference (P =.0077; ANCOVA on modified intent-to-treat population = 115 patients with at least 3 days of pain assessments). Reasons for withdrawing patients from the trial were adverse events in six patients (7.6%) receiving gabapentin and in three patients receiving placebo (7.3%).
                Gabapentin is effective in improving analgesia in patients with neuropathic cancer pain already treated with opioids. Calcitonin was effective in a study of acute phantom limb pain, but it was not studied in the chronic phase. The overall literature on N-methyl-D-aspartate antagonists is equivocal. We tested the hypothesis that calcitonin, ketamine, and their combination are effective in treating chronic phantom limb pain. Our secondary aim was to improve our understanding of the mechanisms of action of the investigated drugs using quantitative sensory testing.
                Twenty patients received, in a randomized, double-blind, crossover manner, 4 i.v. infusions of: 200 IE calcitonin; ketamine 0.4 mg/kg (only 10 patients); 200 IE of calcitonin combined with ketamine 0.4 mg/kg; placebo, 0.9% saline. Intensity of phantom pain (visual analog scale) was recorded before, during, at the end, and the 48 h after each infusion. Pain thresholds after electrical, thermal, and pressure stimulation were recorded before and during each infusion.
                Ketamine, but not calcitonin, reduced phantom limb pain. The combination was not superior to ketamine alone. There was no difference in basal pain thresholds between the amputated and contralateral side except for pressure pain. Pain thresholds were unaffected by calcitonin. The analgesic effect of the combination of calcitonin and ketamine was associated with a significant increase in electrical thresholds, but with no change in pressure and heat thresholds.
                Our results question the usefulness of calcitonin in chronic phantom limb pain and stress the potential interest of N-methyl-D-aspartate antagonists. Sensory assessments indicated that peripheral mechanisms are unlikely important determinants of phantom limb pain. Ketamine, but not calcitonin, affects central sensitization processes that are probably involved in the pathophysiology of phantom limb pain. A controlled clinical trial on the efficacy of a nortriptyline-fluphenazine combination was carried out in patients with painful diabetic polyneuropathy. A visual analog scale was used to evaluate the relief of pain or paresthesia. Significant relief of both pain and paresthesia was obtained with this combination. The differences were statistically significant. Side effects were frequent but not usually severe enough to lead to cessation of these medications. Combination of drugs with different mechanisms of action helps in achieving synergistic analgesic effect in neuropathic pain. Keeping this point in view, the effect and safety aspects of sodium valproate and GTN were assessed alone as well as in combination in this study.
                Prospective double-blind randomized placebo-controlled study.
                Eighty-seven type 2 diabetics with painful neuropathy were enrolled. Four were excluded: three with HbA1c>11 while one withdrew consent. The remaining 83 were given either sodium valproate and GTN spray (group A) or placebo drug and GTN spray (group B) or sodium valproate and placebo spray (group C) or placebo drug and placebo spray (group D). Quantitative assessment of pain was done by McGill pain questionnaire, visual analogue score (VAS) and present pain intensity (PPI) at the beginning of the study and after 3 months along with motor and sensory nerve conduction velocities measurements.
                All the three treatment groups experienced significant improvement in pain score in their drug phase of trial (p<0.001/<0.05) along with some of the electrophysiological parameters. The assessment of the magnitude of therapeutic effect of sodium valproate, GTN and their combination gave numbers needed to treat (NNT) of 7, 5 and 4, respectively.
                Sodium valproate and GTN are well tolerated and provide significant improvement in pain scores as well as in electrophysiological parameters. A double-blind, randomized, placebo-controlled 3-week study evaluated the efficacy of topical 2% amitriptyline, 1% ketamine, and a combination of both in treating patients with neuropathic pain.
                Ninety-two patients with diabetic neuropathy, postherpetic neuralgia, or postsurgical/posttraumatic neuropathic pain with allodynia, hyperalgesia, or pinprick hypesthesia were randomly assigned to receive one of four creams (placebo, 2% amitriptyline, 1% ketamine, or 2% amitriptyline-1% ketamine combined). The primary outcome measure was change in average daily pain intensity (baseline week vs. final week) using an 11-point numerical pain rating scale. Secondary outcomes included the McGill Pain Questionnaire, measures of allodynia and hyperalgesia, and patient satisfaction.
                A reduction in pain scores of 1.1-1.5 units was observed in all groups, and there was no difference between groups. Blood concentrations revealed no significant systemic absorption. Minimal side effects were encountered.
                This randomized, placebo-controlled trial examining topical 2% amitriptyline, 1% ketamine, and a combination in the treatment of neuropathic pain revealed no difference between groups. Optimization of doses may be required, because another study has revealed that higher concentrations of these agents combined do produce significant analgesia. Neuropathic pain remains one of the most challenging pain syndromes; under-diagnosed, poorly managed and associated with significant co-morbidity. With standard therapeutic treatments, responders rarely exceed 50% pain relief and the majority suffer from residual pain. Titration to optimum dose is often limited by dose-related adverse events.
                This randomized, double-blind, placebo-controlled study assessed the potential benefit of adding oxycodone (OxyContin tablets) to gabapentin. The primary endpoint was to evaluate the analgesic efficacy of co-administration of gabapentin and prolonged-release oxycodone, whilst also evaluating the use of escape medication, sleep quality and global assessment of pain.
                Three hundred and thirty eight patients with moderate to severe painful diabetic neuropathy despite receiving their maximum tolerated dose of gabapentin, had oral prolonged-release oxycodone or placebo tablets added to their therapy for up to 12 weeks.
                Oxycodone-gabapentin reduced pain score by 33% from baseline to end of treatment. The overall treatment effect was greater with oxycodone-gabapentin than with placebo-gabapentin (P = 0.007). Oxycodone-gabapentin also significantly improved pain relief vs gabapentin alone (P = 0.003). Oxycodone-gabapentin co-administration was associated with less escape medication use (P = 0.03) and fewer nights of disturbed sleep (P < 0.05). Discontinuations due to lack of therapeutic effect were much lower (14% vs 54%) with oxycodone-gabapentin. The commonly seen opiate-induced adverse events were not exacerbated by the combination of oxycodone and gabapentin.
                This study provides the first evidence that co-administration of prolonged-release oxycodone and existing gabapentin therapy has a clinically meaningful effect in painful diabetic neuropathy. Chemotherapy-induced peripheral neuropathy (CIPN) is a troublesome chronic symptom that has no proven pharmacologic treatment. The purpose of this double-blind randomized placebo-controlled trial was to evaluate a novel compounded topical gel for this problem.
                Patients with CIPN were randomized to baclofen 10 mg, amitriptyline HCL 40 mg, and ketamine 20 mg in a pluronic lecithin organogel (BAK-PLO) versus placebo (PLO) to determine its effect on numbness, tingling, pain, and function. The primary endpoint was the baseline-adjusted sensory subscale of the EORTC QLQ-CIPN20, at 4 weeks.
                Data in 208 patients reveal a trend for improvement that is greater in the BAK-PLO arm over placebo in both the sensory (p = 0.053) and motor subscales (p = 0.021). The greatest improvements were related to the symptoms of tingling, cramping, and shooting/burning pain in the hands as well as difficulty in holding a pen. There were no undesirable toxicities associated with the BAK-PLO and no evidence of systemic toxicity.
                Topical treatment with BAK-PLO appears to somewhat improve symptoms of CIPN. This topical gel was well tolerated, without evident systemic toxicity. Further research is needed with increased doses to better clarify the clinical role of this treatment in CIPN. Drugs 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.
                In 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.
                45 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.
                Combined 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.
                Canadian Institutes of Health Research. The aim of this randomized double-blind, placebo-controlled, parallel-group study was to evaluate the efficacy, safety, and tolerability of pregabalin in combination with oxycodone or placebo, in patients with either postherpetic neuralgia (PHN) or painful diabetic neuropathy (PDN). After a 7-day washout period, 62 patients were randomized to receive either oxycodone mixture 10 mg/day or placebo mixture for 1 week. Patients were then started on open-label pregabalin (75, 150, 300 and 600 mg/day) according to a forced titration dosing regimen, while continuing the same dosage of oxycodone or placebo for 4 weeks. The primary efficacy measure was a decrease in the pain-intensity score of at least 2cm and a pain score <4cm measured using a 10-cm visual analogue scale (VAS) following pregabalin dosage escalation and treatment for 4 weeks. Secondary efficacy measures included sleep interference and the Neuropathic Pain Scale. There were similar levels of overall efficacy between pregabalin/oxycodone and pregabalin/placebo groups in relieving PHN and PDN related pain.
                Peripheral neuropathic pain presents commonly in clinical practice, and 2 of its most prevalent types are PHN and PDN. Currently available treatments provide some degree of pain relief in approximately 40-60% of patients, leaving the remainder with unremitting pain. Although this study supports the effectiveness of pregabalin in the treatment of PHN or PDN, it also shows that the addition of a low dose of oxycodone at 10mg/day does not enhance the pain-relieving effects of pregabalin.
                Copyright 2010 American Pain Society. Published by Elsevier Inc. All rights reserved.
Multiple, good-quality studies demonstrate superior efficacy of two-drug combinations. However, the number of available studies for any one specific combination, as well as other study factors (e.g. limited trial size and duration), preclude the recommendation of any one specific drug combination for neuropathic pain. Demonstration of combination benefits by several studies together with reports of widespread clinical polypharmacy for neuropathic pain surely provide a rationale for additional future rigorous evaluations. In order to properly identify specific drug combinations which provide superior efficacy and/or safety, we recommend that future neuropathic pain studies of two-drug combinations include comparisons with placebo and both single-agent components. Given the apparent adverse impact of combining agents with similar adverse effect profiles (e.g. CNS depression), the anticipated development and availability of non-sedating neuropathic pain agents could lead to the identification of more favourable analgesic drug combinations in which side effects are not compounded.