Oral valdecoxib and injected parecoxib for acute postoperative pain: a quantitative systematic review

BACKGROUND: Clinical trials suggest that cyclo-oxygenase-2 specific inhibitors (coxibs) are an effective treatment for acute postoperative pain. The aims of this systematic review were to examine the evidence for oral valdecoxib and injected parecoxib, and quantify efficacy and adverse effects. METHODS: Information from randomized, double-blind studies in acute postoperative pain was sought. The area under the pain relief versus time curve over four to six hours was dichotomized using validated equations to derive the proportion of patients with treatment and placebo with at least 50% pain relief over four to six hours and calculate the number-needed-to-treat (NNT). Information on duration of analgesia and adverse events was also collected. RESULTS: The NNT for one patient to experience at least 50% relief over six hours following a single oral dose of valdecoxib 20 mg and 40 mg was 1.7 (1.4 to 2.0) and 1.6 (1.4 to 1.8) respectively. The NNT for one patient to have at least 50% relief over four to six hours with parecoxib 20 mg IV and 40 mg IV was 3.0 (2.3 to 4.1) and 2.3 (2.0 to 2.6) respectively. Mean time to remedication (weighted by trial size) was >24 hours with valdecoxib 40 mg, 8.7 hours with parecoxib 40 mg IV and 1.7 to 1.8 hours with placebo. There were no statistical differences between treatment and placebo for any adverse effect. CONCLUSION: Both oral valdecoxib and injected parecoxib are effective treatments for acute postoperative pain.     

Single-dose oral naproxen for acute postoperative pain: a quantitative systematic review

BACKGROUND: Naproxen and naproxen sodium are non-steroidal anti-inflammatory drugs used in a variety of painful conditions, including the treatment of postoperative pain. This review aims to assess the efficacy, safety and duration of action of a single oral dose of naproxen/naproxen sodium for moderate to severe acute postoperative pain in adults, compared with placebo. METHODS: The Cochrane Library (issue 4 2002), EMBASE, PubMed, MEDLINE and an in-house database were searched for randomised, double blind, placebo controlled trials of a single dose of orally administered naproxen or naproxen sodium in adults with acute postoperative pain. Pain relief or pain intensity data were extracted and converted into dichotomous information to give the number of patients with at least 50% pain relief over 4 to 6 hours. Relative benefit and number-needed-to-treat were then calculated. The percentage of patients with any adverse event, number-needed-to-harm, and time to remedication were also calculated. RESULTS: Ten trials with 996 patients in met the inclusion criteria. Six trials compared naproxen sodium 550 mg (252 patients) with placebo (248 patients); the NNT for at least 50% pain relief over six hours was 2.6 (95% confidence interval 2.2 to 3.2). There was no significant difference between the number of patients experiencing any adverse event on treatment compared with placebo. Weighted mean time to remedication was 7.6 hours for naproxen sodium 550 mg (206 patients) and 2.6 hours for placebo (205 patients). Four other trials used lower doses. CONCLUSION: A single oral dose of naproxen sodium 550 mg is an effective analgesic in the treatment of acute postoperative pain. A low incidence of adverse events was found, although these were not reported consistently.     

Duloxetine for painful diabetic neuropathy and fibromyalgia pain: systematic review of randomised trials

Background

Duloxetine hydrochloride is a reuptake inhibitor of 5-hydroxytryptamine and norepinephrine used to treat depression, generalized anxiety disorder, neuropathic pain, and stress incontinence in women. We investigated the efficacy of duloxetine in painful diabetic neuropathy and fibromyalgia to allow comparison with other antidepressants.

Methods

We searched PubMed, EMBASE (via Ovid), and Cochrane CENTRAL up to June 2008 for randomised controlled trials using duloxetine to treat neuropathic pain.

Results

We identified six trials with 1,696 patients: 1,510 were treated with duloxetine and 706 with placebo. All patients had established baseline pain of at least moderate severity. Trial duration was 12 to 13 weeks. Three trials enrolled patients with painful diabetic neuropathy (PDN) and three enrolled patients with fibromyalgia. The number needed to treat (NNT) for at least 50% pain relief at 12 to 13 weeks with duloxetine 60 mg versus placebo (1,211 patients in the total comparison) was 5.8 (95% CI 4.5 to 8.4), and for duloxetine 120 mg (1,410 patients) was 5.7 (4.5 to 5.7). There was no difference in NNTs between PDN and fibromyalgia. With all doses of duloxetine combined (20/60/120 mg) there were fewer withdrawals for lack of efficacy than with placebo (number needed to treat to prevent one withdrawal 20 (13 to 42)), but more withdrawals due to adverse events (number needed to harm (NNH) 15 (11 to 25)). Nausea, somnolence, constipation, and reduced appetite were all more common with duloxetine than placebo (NNH values 6.3, 11, 11, and 18 respectively). The results for duloxetine are compared with published data for other antidepressants in neuropathic pain.

Conclusion

Duloxetine is equally effective for the treatment of PDN and fibromyalgia, judged by the outcome of at least 50% pain relief over 12 weeks, and is well tolerated. The NNT of 6 for 50% pain relief suggests that this is likely to be a useful drug in these difficult-to-treat conditions, where typically only a minority of patients respond. Comparing duloxetine with antidepressants for pain relief in DPN shows inadequacies in the evidence for efficacy of antidepressants, which are currently recommended in PDN care pathways.

     

Tolerability and adverse events in clinical trials of celecoxib in osteoarthritis and rheumatoid arthritis: systematic review and meta-analysis of information from company clinical trial reports

The objective was to improve understanding of adverse events occurring with celecoxib in the treatment of osteoarthritis and rheumatoid arthritis. Data were extracted from company clinical trial reports of randomised trials of celecoxib in osteoarthritis or rheumatoid arthritis lasting 2 weeks or more. Outcomes were discontinuations (all cause, lack of efficacy, adverse event, gastrointestinal adverse event), endoscopically detected ulcers, gastrointestinal or cardio-renal events, and major changes in haematological parameters. The main comparisons were celecoxib (all doses) versus placebo, paracetamol (acetaminophen) 4,000 mg daily, rofecoxib 25 mg daily, or nonsteroidal anti-inflammatory drugs (NSAIDs) (naproxen, diclofenac, ibuprofen, and loxoprofen). For NSAIDs, celecoxib was compared both at all doses and at licensed doses (200 to 400 mg daily). Thirty-one trials included 39,605 randomised patients. Most patients had osteoarthritis and were women of average age 60 years or above. Most trials lasted 12 weeks or more. Doses of celecoxib were 50 to 800 mg/day. Compared with placebo, celecoxib had fewer discontinuations for any cause or for lack of efficacy, fewer serious adverse events, and less nausea. It had more patients with dyspepsia, diarrhoea, oedema, more adverse events that were gastrointestinal or treatment related, and more patients experiencing an adverse event. There were no differences for hypertension, gastrointestinal tolerability, or discontinuations for adverse events. Compared with paracetamol, celecoxib had fewer discontinuations for any cause, for lack of efficacy, or diarrhoea, but no other differences. Compared with rofecoxib, celecoxib had fewer patients with abdominal pain and oedema, but no other differences. Compared with NSAIDs, celecoxib had fewer symptomatic ulcers and bleeds, endoscopically detected ulcers, and discontinuations for adverse events or gastrointestinal adverse events. Fewer patients had any, or a gastrointestinal, or a treatment-related adverse event, or vomiting, abdominal pain, dyspepsia, or reduced haemoglobin or haematocrit. Discontinuations for lack of efficacy were higher. No differences were found for all-cause discontinuations, serious adverse events, hypertension, diarrhoea, nausea, oedema, myocardial infarction, cardiac failure, or raised creatinine. Company clinical trial reports present much more information than published papers. Adverse event information is clearly presented in company clinical trial reports, which are an ideal source of information for systematic review and meta-analysis.     

Systematic review of dexketoprofen in acute and chronic pain

Background

Dexketoprofen, an NSAID used in the management of acute and chronic pains, is licensed in several countries but has not previously been the subjected of a systematic review. We used published and unpublished information from randomised clinical trials (RCTs) of dexketoprofen in painful conditions to assess evidence on efficacy and harm.

Methods

PubMed and Cochrane Central were searched for RCTs of dexketoprofen for pain of any aetiology. Reference lists of retrieved articles and reviews were also searched. Menarini Group produced copies of published and unpublished studies (clinical trial reports). Data were abstracted into a standard form. For studies reporting results of single dose administration, the number of patients with at least 50% pain relief was derived and used to calculate the relative benefit (RB) and number-needed-to-treat (NNT) for one patient to achieve at least 50% pain relief compared with placebo.

Results

Thirty-five trials were found in acute pain and chronic pain; 6,380 patients were included, 3,381 receiving dexketoprofen. Information from 16 trials (almost half the total patients) was obtained from clinical trial reports from previously unpublished trials or abstracts. Almost all of the trials were of short duration in acute conditions or recent onset pain. All 12 randomised trials that compared dexketoprofen (any dose) with placebo found dexketoprofen to be statistically superior. Five trials in postoperative pain yielded NNTs for 12.5 mg dexketoprofen of 3.5 (2.7 to 4.9), 25 mg dexketoprofen of 3.0 (2.4 to 3.9), and 50 mg dexketoprofen of 2.1 (1.5 to 3.5). In 29/30 active comparator trials, dexketoprofen at the dose used was at least equivalent in efficacy to comparator drugs. Adverse event withdrawal rates were low in postoperative pain and somewhat higher in trials of longer duration; no serious adverse events were reported.

Conclusion

Dexketoprofen was at least as effective as other NSAIDs and paracetamol/opioid combinations. While adverse event withdrawal was not different between dexketoprofen and comparator analgesics, the different conditions and comparators studies precluded any formal analysis. Exposure was limited, and no conclusions could be drawn about safety in terms of serious adverse events like gastrointestinal bleeding or cardiovascular events.     

Comparative Efficacy and Safety of Different Antiplatelet Agents for Prevention of Major Cardiovascular Events and Leg Amputations in Patients with Peripheral Arterial Disease: A Systematic Review and Network Meta-Analysis

There is a lack of consensus regarding which type of antiplatelet agent should be used in patients with peripheral arterial disease (PAD) and little is known on the advantages and disadvantages of dual antiplatelet therapy. We conducted a systematic review and network meta-analysis of available randomized controlled trials (RCT) comparing different antiplatelet drugs (Aspirin, Ticlopidine, Clopidogrel, Ticagrelor, Cilostazol, Picotamide and Vorapaxar as monotherapies or in combination with aspirin) in PAD patients (PROSPERO public database; CRD42014010299).We collated evidence from previous relevant meta-analyses and searched online databases. Primary efficacy endpoints were: (1) the composite rate of major adverse cardiovascular events (MACE; including vascular deaths, non-fatal myocardial infarction and non-fatal stroke), and (2) the rate of major leg amputations. The primary safety endpoint was the rate of severe bleeding events. Bayesian models were employed for multiple treatment comparisons and risk-stratified hierarchies of comparative efficacy were produced to aid medical decision making. Number-Needed-to-Treat (NNT) and Number-Needed-to-Harm (NNH) are reported in case of significant results. We analyzed 49 RCTs comprising 34,518 patients with 88,358 person-years of follow-up with placebo as reference treatment. Aspirin, Cilostazol, Vorapaxar and Picotamide were ineffective in reducing MACE. A significant MACE reduction was noted with Ticagrelor plus aspirin (RR: 0.67; 95%CrI: 0.46–0.96, NNT = 66), Clopidogrel (RR: 0.72; 95%CrI: 0.58–0.91, NNT = 80), Ticlopidine (RR: 0.75; 95%CrI: 0.58–0.96, NNT = 87), and Clopidogrel plus aspirin (RR: 0.78; 95%CrI: 0.61–0.99, NNT = 98). Dual antiplatelet therapy with Clopidogrel plus aspirin significantly reduced major amputations following leg revascularization (RR: 0.68; 95%CrI: 0.46–0.99 compared to aspirin, NNT = 94). The risk of severe bleeding was significantly higher with Ticlopidine (RR: 5.03; 95%CrI: 1.23–39.6, NNH = 25), Vorapaxar (RR: 1.80; 95%CrI: 1.22–2.69, NNH = 130), and Clopidogrel plus aspirin (RR: 1.48; 95%CrI: 1.05–2.10, NNH = 215). Clopidogrel monotherapy showed the most favourable benefit-harm profile (79% cumulative rank probability best and 77% cumulative rank probability safest). In conclusion, Clopidogrel should be the indicated antiplatelet agent in PAD patients. Dual antiplatelet therapy with aspirin and Clopidogrel can reduce the rate of major leg amputations following revascularization, but carries a slightly higher risk of severe bleeding.     

Oral acyclovir in acute herpes zoster.

Oral acyclovir at a dose of 800 mg five times daily for seven days was compared with placebo in a randomised double blind trial conducted at three centres in the United Kingdom. The study group comprised 205 elderly immune competent patients suffering from herpes zoster who were entered within 72 hours of the onset of rash. Acyclovir significantly reduced the times to arrest of new lesion formation (p = 0.005), loss of vesicles (p less than 0.001), and full crusting (p = 0.02) in those patients entered within 48 hours of the onset of rash. In addition, there was a significant reduction in pain during treatment with acyclovir as compared with placebo (p = 0.008). Of the patients with severe pain on entry, 40% (10/25) of those treated with acyclovir had no or only mild pain at the end of treatment, whereas in the placebo group all had residual moderate or severe pain (p less than 0.001). No clinically important adverse effects of acyclovir were reported. Oral acyclovir may modify acute herpes zoster and reduce pain.     

Rofecoxib and tramadol do not attenuate delayed-onset muscle soreness or ischaemic pain in human volunteers

We assessed the effect of rofecoxib, a cyclo-oxygenase-2 inhibitor, and tramadol, a centrally acting analgesic, on both delayed-onset muscle soreness (DOMS) and experimentally induced ischaemic pain. We induced DOMS in 10 male and 5 female healthy volunteers by downhill running for 30 min at a 12% decline and a speed of 9 km x h(-1). We also induced ischaemic pain by finger movements with an arterial tourniquet around the arm. In a randomized, double-blind crossover format, we administered rofecoxib (50 mg, daily), tramadol (50 mg, 3 times per day), and a placebo (orally for 3 days), starting immediately after exercise. A 100 mm visual analogue scale (VAS) and McGill pain questionnaire were used to describe muscle soreness and ischaemic forearm pain 24 h after the exercise. The pressure pain threshold (PPT) in the thigh and ischaemic pain tolerance in the forearm were measured before exercise and 24 and 72 h after exercise. PPT decreased 24 h after exercise, compared with pre-exercise values (ANOVA, p < 0.05), but neither drug had any significant effect on the PPT. Neither rofecoxib nor tramadol had any effect on time of ischaemia tolerated or amount of finger activity during ischaemia. The VAS and pain-rating index, for both muscle soreness and experimental ischaemic pain, were not affected significantly by either drug. Both DOMS and ischaemic pain share peripheral and central mechanisms, yet neither are attenuated by rofecoxib or tramadol.     

Comparative Analgesic Activity of Levomepromazine and Morphine in Patients with Chronic Pain

Apart from its ability to potentiate the action of narcotics, levomepromazine, a phenothiazine derivative, was shown to possess its own analgesic activity comparable to that of morphine at a 3:2 dose relationship.In a double-blind crossover study of 18 patients suffering from chronic pain (cancer and arthritis), levomepromazine (15 mg.) was compared with morphine (10 mg.) and placebo. Three hours after intramuscular administration, levomepromazine proved to be significantly superior to placebo (p < .05) and indistinguishable from morphine. Evaluations of pain relief by estimations of changes in pain intensity were found to correlate well with evaluations based on recognition of pain relief exceeding 50%.The potent analgesic effect of levomepromazine was obtained at the price of excessive sedation. This, however, was considered an acceptable side effect in a patient suffering from chronic pain. These results provide encouragement in the quest for a non-addicting substitute for morphine.     

A 1-year follow-up after a pilot study with Doloteffin for low back pain.

OBJECTIVE: To complete a year's follow-up on patients from a 6-week double-blind pilot comparison between 44 Doloteffin patients and 44 rofecoxib patients being treated for acute exacerbations of chronic low back pain. METHODS: 38 "ex-Doloteffin" (ex-D) and 35 "ex-rofecoxib" (ex-R) received Doloteffin containing 60 mg harpagoside per day for up to 54 weeks. Pain, additional analgesics, mobility, general health and adverse events were assessed from diary records and at 6-week visits. RESULTS: 53 patients remained in the follow-up at 24 weeks and 43 at 54 weeks. There was never any convincing difference between ex-D and ex-R patients in the number of patients remaining in follow-up, diary pain scores, additional analgesics, Arhus Index and health assessment questionnaire scores (HAQ). Individual fluctuations notwithstanding, the follow-up showed a slight overall improvement on the improvements in Arhus and HAQ scores achieved in the pilot study (MANOVA p = 0.016). Of the 21761 patient-days, the respective percentages with no, mild, moderate, severe and excruciating pain were 28%, 39%, 22%, 8.5% and 1.5%, respectively. Few patients requested additional treatments for their pain. Three patients suffered from minor adverse drug reactions. CONCLUSION: Long-term treatment with Doloteffin was well tolerated. Ex-R and ex-D patients behaved similarly during the follow-up.     

Cannabinoids for control of chemotherapy induced nausea and vomiting: quantitative systematic review

ObjectiveTo quantify the antiemetic efficacy and adverse effects of cannabis used for sickness induced by chemotherapy.DesignSystematic review.Studies30 randomised comparisons of cannabis with placebo or antiemetics from which dichotomous data on efficacy and harm were available (1366 patients). Oral nabilone, oral dronabinol (tetrahydrocannabinol), and intramuscular levonantradol were tested. No cannabis was smoked. Follow up lasted 24 hours.ResultsCannabinoids were more effective antiemetics than prochlorperazine, metoclopramide, chlorpromazine, thiethylperazine, haloperidol, domperidone, or alizapride: relative risk 1.38 (95% confidence interval 1.18 to 1.62), number needed to treat 6 for complete control of nausea; 1.28 (1.08 to 1.51), NNT 8 for complete control of vomiting. Cannabinoids were not more effective in patients receiving very low or very high emetogenic chemotherapy. In crossover trials, patients preferred cannabinoids for future chemotherapy cycles: 2.39 (2.05 to 2.78), NNT 3. Some potentially beneficial side effects occurred more often with cannabinoids: “high” 10.6 (6.86 to 16.5), NNT 3; sedation or drowsiness 1.66 (1.46 to 1.89), NNT 5; euphoria 12.5 (3.00 to 52.1), NNT 7. Harmful side effects also occurred more often with cannabinoids: dizziness 2.97 (2.31 to 3.83), NNT 3; dysphoria or depression 8.06 (3.38 to 19.2), NNT 8; hallucinations 6.10 (2.41 to 15.4), NNT 17; paranoia 8.58 (6.38 to 11.5), NNT 20; and arterial hypotension 2.23 (1.75 to 2.83), NNT 7. Patients given cannabinoids were more likely to withdraw due to side effects 4.67 (3.07 to 7.09), NNT 11.ConclusionsIn selected patients, the cannabinoids tested in these trials may be useful as mood enhancing adjuvants for controlling chemotherapy related sickness. Potentially serious adverse effects, even when taken short term orally or intramuscularly, are likely to limit their widespread use.

What is already known on this topic

Requests have been made for legalisation of cannabis (marijuana) for medical useLong term smoking of cannabis can have physical and neuropsychiatric adverse effectsCannabis may be useful in the control of chemotherapy related sickness

What this study adds

Oral nabilone and dronabinol and intramuscular levonantradol are superior to conventional antiemetics (such as prochlorperazine or metoclopramide) in chemotherapySide effects are common with cannabinoids, and although some may be potentially beneficial (euphoria, “high,” sedation), others are harmful (dysphoria, depression, hallucinations)Many patients have a strong preference for cannabinoids     

First-dose analgesic effect of the cyclo-oxygenase-2 selective inhibitor lumiracoxib in osteoarthritis of the knee: a randomized, double-blind, placebo-controlled comparison with celecoxib [NCT00267215]

Cyclo-oxygenase-2 selective inhibitors are frequently used to manage osteoarthritis. We compared the analgesic efficacy of the novel cyclo-oxygenase-2 selective inhibitor lumiracoxib (Prexige) versus placebo and celecoxib in patients with knee osteoarthritis. This seven day, double-blind, placebo and active comparator controlled, parallel group study included 364 patients aged > or = 50 years with moderate-to-severe symptomatic knee osteoarthritis. Patients received lumiracoxib 400 mg/day (four times the recommended chronic dose in osteoarthritis; n = 144), placebo (n = 75), or celecoxib 200 mg twice daily (n = 145). The primary variable was actual pain intensity difference (100 mm visual-analogue scale) between baseline and the mean of three hour and five hour assessments after the first dose. Actual pain intensity difference, average and worst pain, pain relief and functional status (Western Ontario and McMaster Universities Osteoarthritis Index [WOMAC]) were measured over seven days. Patients also completed a global evaluation of treatment effect at study end or premature discontinuation. For the primary variable, the superiority of lumiracoxib versus placebo, the noninferiority of lumiracoxib versus celecoxib, and the superiority of lumiracoxib versus celecoxib were assessed by closed test procedure adjusting for multiplicity, thereby maintaining the overall 5% significance level. In addition, celecoxib was assessed versus placebo in a predefined exploratory manner to assess trial sensitivity. Lumiracoxib provided better analgesia than placebo 3-5 hours after the first dose (P = 0.004) through to study end. The estimated difference between lumiracoxib and celecoxib 3-5 hours after the first dose was not significant (P = 0.185). Celecoxib was not significantly different from placebo in this analysis (P = 0.069). At study end 13.9% of lumiracoxib-treated patients reported complete pain relief versus 5.5% and 5.3% of celecoxib and placebo recipients, respectively. WOMAC total and subscales improved for both active treatments versus placebo except for difficulty in performing daily activities, for which celecoxib just failed to achieve significance (P = 0.056). In the patient's global evaluation of treatment effect, 58.1% of patients receiving lumiracoxib rated treatment as 'excellent' or 'good', versus 48.6% of celecoxib and 25.3% of placebo patients. Lumiracoxib was well tolerated. The overall incidence of adverse events was similar across treatment groups.     

Comparative evaluation of various analgesics in reducing pain in irreversible pulpitis

It is of interest to evaluate a single dose of three different analgesics compared to placebo in patients with symptomatic irreversible pulpitis. 120 patients were enrolled with severe pain in this prospective clinical trial. Patients were randomly divided into four groups after shaping and cleaning of root canals. This includes placebo, piroxicam 20mg, acetaminophen 325mg with aceclofenac sodium 100mg and acetaminophen 650mg. Participants were given a questionnaire to note the pain scores at various time intervals (6 hrs, 12 hrs, and 24 hrs) along with the respective tablets in a concealed manner. Data thus collected was analyzed for statistical significance. The severity of pain decreased in all the three interventional groups compared to the control group (p <0.01) at 6 hours. Zerodol-P and dolonex showed better pain reduction in comparison to the placebo and dolo 650 group (p <0.05) at 12 and 24 hours. Data shows that both zerodol-P and dolonex groups had similar effects at all time intervals. Thus, a single dose of analgesic such as Zerodol-P and Dolonex following shaping and cleaning of root canals relieved pain at all time intervals of the treatment. However, Dolo 650 performed better during the initial 6hrs after completion of the shaping and cleaning of root canals compared to the placebo.     

Quantitative systematic review of topically applied non-steroidal anti-inflammatory drugs.

OBJECTIVE: To review the effectiveness and safety of topical non-steroidal anti-inflammatory drugs in acute and chronic pain conditions. DESIGN: Quantitative systematic review of randomised controlled trials. DATA SOURCES: 86 trials involving 10,160 patients. MAIN OUTCOME MEASURES: Measures of treatment success approximating at least 50% reduction in pain, local and systemic adverse effects. Analysis at 1 week for acute and 2 weeks for chronic conditions with relative benefit and number needed to treat. RESULTS: In acute pain conditions (soft tissue trauma, strains, and sprains) placebo controlled trials had a relative benefit of 1.7 (1.5 to 1.9), the number needed to treat was 3.9 (3.4 to 4.4). With analysis by drug (at least three trials), ketoprofen (number needed to treat 2.6), felbinac (3.0), ibuprofen (3.5), and piroxicam (4.2) had significant efficacy. Benzydamine and indomethacin were no different from placebo. In chronic pain conditions (osteoarthritis, tendinitis) placebo controlled trials had a relative benefit of 2.0 (1.5 to 2.7); the number needed to treat was 3.1 (2.7 to 3.8). Small trials (< 40 treated patients) exaggerated effectiveness of topical non-steroidals by 33% in acute conditions but not in chronic conditions. There was no relation between trial quality and treatment effect. In both acute and chronic pain local and systemic adverse events and withdrawal from the study related to the drug had a low incidence and were no different from placebo. CONCLUSION: Topical non-steroidal anti-inflammatory drugs are effective in relieving pain in acute and chronic conditions.     

Does the cannabinoid dronabinol reduce central pain in multiple sclerosis? Randomised double blind placebo controlled crossover trial

Objective To evaluate the effect of the oral synthetic δ-9-tetrahydrocannabinol dronabinol on central neuropathic pain in patients with multiple sclerosis.Design Randomised double blind placebo controlled crossover trial.Setting Outpatient clinic, University Hospital of Aarhus, Denmark.Participants 24 patients aged between 23 and 55 years with multiple sclerosis and central pain.Intervention Orally administered dronabinol at a maximum dose of 10 mg daily or corresponding placebo for three weeks (15-21 days), separated by a three week washout period.Main outcome measure Median spontaneous pain intensity (numerical rating scale) in the last week of treatment.Results Median spontaneous pain intensity was significantly lower during dronabinol treatment than during placebo treatment (4.0 (25th to 75th centiles 2.3 to 6.0) v 5.0 (4.0 to 6.4), P = 0.02), and median pain relief score (numerical rating scale) was higher (3.0 (0 to 6.7) v> 0 (0 to 2.3), P = 0.035). The number needed to treat for 50% pain relief was 3.5 (95% confidence interval 1.9 to 24.8). On the SF-36 quality of life scale, the two items bodily pain and mental health indicated benefits from active treatment compared with placebo. The number of patients with adverse events was higher during active treatment, especially in the first week of treatment. The functional ability of the multiple sclerosis patients did not change.Conclusions Dronabinol has a modest but clinically relevant analgesic effect on central pain in patients with multiple sclerosis. Adverse events, including dizziness, were more frequent with dronabinol than with placebo during the first week of treatment.     

Analgesic efficacy and safety of paracetamol-codeine combinations versus paracetamol alone: a systematic review.

OBJECTIVES--To assess whether adding codeine to paracetamol has an additive analgesic effect; to assess the safety of paracetamol-codeine combinations versus paracetamol alone. DESIGN--Systematic literature review with meta-analysis, methodological quality of published trials being scored by means of 13 predefined criteria. TRIALS--24 of 29 trials that met the inclusion criteria. Models studied in the trials were postsurgical pain (21), postpartum pain (one), osteoarthritic pain (one), and experimentally induced pain (one). INTERVENTIONS--Dosages ranged from 400 to 1000 mg paracetamol and 10 to 60 mg codeine. MAIN OUTCOME MEASURES--The sum pain intensity difference (efficacy analysis) and the proportion of patients reporting a side effect (safety analysis). RESULTS--Most trials were considered of good to very good quality. Only the single dose studies could be combined for analysis of analgesic efficacy. Pooled efficacy results indicated that codeine added to paracetamol provided a 5% increase in analgesia on the sum pain intensity difference. This effect was comparable to the difference in analgesic effect between codeine and placebo. The cumulative incidence of side effects with each treatment was comparable in the single dose trials. In the multidose studies a significantly higher proportion of side effects occurred with paracetamol-codeine preparations. CONCLUSION--The difference is analgesic effect between paracetamol-codeine combinations and paracetamol alone was small but statistically significant. In the multidose studies the proportion of patients reporting a side effect was significantly higher with paracetamol-codeine combinations. For occasional pain relief a paracetamol-codeine combination might be appropriate but repeated use increases the occurrence of side effects.     

Development of musculoskeletal toxicity without clear benefit after administration of PG-116800, a matrix metalloproteinase inhibitor,to patients with knee osteoarthritis: a randomized, 12-month,double-blind,placebo-controlled study

We performed a randomized, double-blind, placebo-controlled, multicenter, parallel-group, dose-response study of the efficacy and safety of the oral administration of PG-116800, a matrix metalloproteinase (MMP) inhibitor, in patients with mild to moderate knee osteoarthritis. The primary efficacy endpoints included the progression of joint space narrowing in the osteoarthritic knee, as measured by microfocal radiography with fluoroscopic positioning, and the reduction of symptoms (pain and stiffness) and/or the improvement of function, as measured by the Western Ontario and McMaster Universities osteoarthritis index (WOMAC). Four hundred and one patients were randomly assigned to either placebo (n = 80) or one of fourdoses of PG-116800: 25 mg (n = 81), 50 mg (n = 80), 100 mg (n = 80), or 200 mg (n = 80) taken twice daily for 12 months. During the study, the 200-mg dose was discontinued based on an increased frequency of musculoskeletal adverse effects. After 1 year of treatment, no statistically significant difference was observed between placebo and PG-116800 with regard to mean changes in minimum joint space width of the knee or to WOMAC scores. The most frequent adverse effect was arthralgia (35%). Twenty-three percent of evaluable patients had at least a 30% decrease from baseline of at least onerange-of-motion measurement of either shoulder at a follow-up visit. The percentage of patients with reduction in range of motion was significantly greater in the twohighest dose groups relative to placebo. Thirteen percent of patients, half of whom were in the 200-mg group, reported hand adverse events (oedema, palmar fibrosis, Dupuytren contracture, or persistent tendon thickness or nodules). The threemost frequent shoulder adverse events were reversible arthralgia, stiffness, and myalgia, which mostly affected the twohighest dose groups. The unfavorable risk-benefit balance of the MMP inhibitor PG-116800 in patients with knee osteoarthritis precludes further development of the compound for this indication. This study adds to the weight of evidence suggesting that side effect profiles of MMP inhibitors in general make them unsuitable for use in osteoarthritis.     

Lidocaine patch (5%) is no more potent than placebo in treating chronic back pain when tested in a randomised double blind placebo controlled brain imaging study

ABSTRACT: The 5% Lidocaine patch is used for treating chronic neuropathic pain conditions such as chronic back pain (CBP), diabetic neuropathy and complex regional pain syndrome, but is effective in a variable proportion of patients. Our lab has reported that this treatment reduces CBP intensity and associated brain activations when tested in an open labelled preliminary study. Notably, effectiveness of the 5% Lidocaine patch has not been tested against placebo for treating CBP. In this study, effectiveness of the 5% Lidocaine patch was compared with placebo in 30 CBP patients in a randomised double-blind study where 15 patients received 5% Lidocaine patches and the remaining patients received placebo patches. Functional MRI was used to identify brain activity for fluctuations of spontaneous pain, at baseline and at two time points after start of treatment (6 hours and 2 weeks). There was no significant difference between the treatment groups in either pain intensity, sensory and affective qualities of pain or in pain related brain activation at any time point. However, 50% patients in both the Lidocaine and placebo arms reported a greater than 50% decrease in pain suggesting a marked placebo effect. When tested against an untreated CBP group at similar time points, the patch treated subjects showed significantly greater decrease in pain compared to the untreated group (n=15). These findings suggest that although the 5% Lidocaine is not better than placebo in its effectiveness for treating pain, the patch itself induces a potent placebo effect in a significant proportion of CBP patients.     

The quality of clinical trials with Harpagophytum procumbens

OBJECTIVE: To examine systematically the quality of the clinical trials investigating the effectiveness of Harpagophytum products. METHODS: Literature searches and enquiries to experts identified 20 studies of treatment with various Harpagophytum products (powder, aqueous and ethanolic extracts) for exacerbations of chronic musculoskeletal pain. Eight were open uncontrolled observational studies, one comparing progress under treatment for pain in back, knee and hip pain. Two were open comparisons with conventional treatment, only one of which was randomised. Ten were double-blinded, randomised controlled comparisons, 8 with placebo and 2 with NSAID comparator treatments. Indices of the internal and external validities were examined by reference to a checklist to see how well the studies answered the questions: do Harpagophytum products work and do they work as well as more conventional comparator treatments? RESULTS: The uncontrolled trials, though providing useful preliminary estimates of the possible effect of treating various conditions, could not separate the effects of the Harpagophytum product from whatever placebo effect might have been exerted in the circumstances of the study. The 2 open comparisons were open to performance, detection and/or selection bias. Of the 8 randomised double blinded controlled comparisons with placebo, 6 were marred by lack of transparency, one could not provide definitive evidence from its pre-selected principal outcome measure, and one provided good quality evidence of a dose dependent superiority of effect over placebo, though this was with a product that is not generally available for clinical practice. One of the randomised controlled comparisons with comparator (Doloteffin versus rofecoxib) was intended only as a pilot and studied too few patients for definitive conclusions whereas the other did provide good evidence that the powder, Harpadol is not importantly less effective than the weak NSAID diacerhein. CONCLUSIONS: Evidence of effectiveness of Harpagophytum products is not transferrable from product to product. The results of some studies suggest some effectiveness for some products, but for none of the clinically available products is the quality of evidence totally satisfactory. It is better so far with products that contain at least 50 mg of harpagoside in the daily dosage than with products (which happen to be of ethanolic extraction) that contain less.     

Chronoeffectiveness of indomethacin in four patients suffering from an evolutive osteoarthritis of hip or knee

During a 4-week span 4 patients suffering from an evolutive osteoarthritis ingested 3 pills/day at fixed clock hours: 0800, 1200 and 2000. One of the weeks was devoted to a (placebo) control span. During the other weeks only one of the 3 ingested pills contained the daily dose of 50 mg indomethacin. This latter, when taken at 1200, had the maximum effect on self-rated pain (decrease of 60% of the 24-h mean, p less than 0.0005) and self-rated stiffness (decrease of 54% of M, p less than 0.005) as well as on mean oral temperature.