Ewan D McNicol

Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis.

BACKGROUND New drug treatments, clinical trials, and standards of quality for assessment of evidence justify an update of evidence-based recommendations for the pharmacological treatment of neuropathic pain. Using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE), we revised the Special Interest Group on Neuropathic Pain (NeuPSIG) recommendations for the pharmacotherapy of neuropathic pain based on the results of a systematic review and meta-analysis. METHODS Between April, 2013, and January, 2014, NeuPSIG of the International Association for the Study of Pain did a systematic review and meta-analysis of randomised, double-blind studies of oral and topical pharmacotherapy for neuropathic pain, including studies published in peer-reviewed journals since January, 1966, and unpublished trials retrieved from ClinicalTrials.gov and websites of pharmaceutical companies. We used number needed to treat (NNT) for 50% pain relief as a primary measure and assessed publication bias; NNT was calculated with the fixed-effects Mantel-Haenszel method. FINDINGS 229 studies were included in the meta-analysis. Analysis of publication bias suggested a 10% overstatement of treatment effects. Studies published in peer-reviewed journals reported greater effects than did unpublished studies (r(2) 9·3%, p=0·009). Trial outcomes were generally modest: in particular, combined NNTs were 6·4 (95% CI 5·2-8·4) for serotonin-noradrenaline reuptake inhibitors, mainly including duloxetine (nine of 14 studies); 7·7 (6·5-9·4) for pregabalin; 7·2 (5·9-9·21) for gabapentin, including gabapentin extended release and enacarbil; and 10·6 (7·4-19·0) for capsaicin high-concentration patches. NNTs were lower for tricyclic antidepressants, strong opioids, tramadol, and botulinum toxin A, and undetermined for lidocaine patches. Based on GRADE, final quality of evidence was moderate or high for all treatments apart from lidocaine patches; tolerability and safety, and values and preferences were higher for topical drugs; and cost was lower for tricyclic antidepressants and tramadol. These findings permitted a strong recommendation for use and proposal as first-line treatment in neuropathic pain for tricyclic antidepressants, serotonin-noradrenaline reuptake inhibitors, pregabalin, and gabapentin; a weak recommendation for use and proposal as second line for lidocaine patches, capsaicin high-concentration patches, and tramadol; and a weak recommendation for use and proposal as third line for strong opioids and botulinum toxin A. Topical agents and botulinum toxin A are recommended for peripheral neuropathic pain only. INTERPRETATION Our results support a revision of the NeuPSIG recommendations for the pharmacotherapy of neuropathic pain. Inadequate response to drug treatments constitutes a substantial unmet need in patients with neuropathic pain. Modest efficacy, large placebo responses, heterogeneous diagnostic criteria, and poor phenotypic profiling probably account for moderate trial outcomes and should be taken into account in future studies. FUNDING NeuPSIG of the International Association for the Study of Pain.

Pharmacotherapy for neuropathic pain in adults

BACKGROUND New drug treatments, clinical trials, and standards of quality for assessment of evidence justify an update of evidence-based recommendations for the pharmacological treatment of neuropathic pain. Using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE), we revised the Special Interest Group on Neuropathic Pain (NeuPSIG) recommendations for the pharmacotherapy of neuropathic pain based on the results of a systematic review and meta-analysis. METHODS Between April, 2013, and January, 2014, NeuPSIG of the International Association for the Study of Pain did a systematic review and meta-analysis of randomised, double-blind studies of oral and topical pharmacotherapy for neuropathic pain, including studies published in peer-reviewed journals since January, 1966, and unpublished trials retrieved from ClinicalTrials.gov and websites of pharmaceutical companies. We used number needed to treat (NNT) for 50% pain relief as a primary measure and assessed publication bias; NNT was calculated with the fixed-effects Mantel-Haenszel method. FINDINGS 229 studies were included in the meta-analysis. Analysis of publication bias suggested a 10% overstatement of treatment effects. Studies published in peer-reviewed journals reported greater effects than did unpublished studies (r(2) 9·3%, p=0·009). Trial outcomes were generally modest: in particular, combined NNTs were 6·4 (95% CI 5·2-8·4) for serotonin-noradrenaline reuptake inhibitors, mainly including duloxetine (nine of 14 studies); 7·7 (6·5-9·4) for pregabalin; 7·2 (5·9-9·21) for gabapentin, including gabapentin extended release and enacarbil; and 10·6 (7·4-19·0) for capsaicin high-concentration patches. NNTs were lower for tricyclic antidepressants, strong opioids, tramadol, and botulinum toxin A, and undetermined for lidocaine patches. Based on GRADE, final quality of evidence was moderate or high for all treatments apart from lidocaine patches; tolerability and safety, and values and preferences were higher for topical drugs; and cost was lower for tricyclic antidepressants and tramadol. These findings permitted a strong recommendation for use and proposal as first-line treatment in neuropathic pain for tricyclic antidepressants, serotonin-noradrenaline reuptake inhibitors, pregabalin, and gabapentin; a weak recommendation for use and proposal as second line for lidocaine patches, capsaicin high-concentration patches, and tramadol; and a weak recommendation for use and proposal as third line for strong opioids and botulinum toxin A. Topical agents and botulinum toxin A are recommended for peripheral neuropathic pain only. INTERPRETATION Our results support a revision of the NeuPSIG recommendations for the pharmacotherapy of neuropathic pain. Inadequate response to drug treatments constitutes a substantial unmet need in patients with neuropathic pain. Modest efficacy, large placebo responses, heterogeneous diagnostic criteria, and poor phenotypic profiling probably account for moderate trial outcomes and should be taken into account in future studies. FUNDING NeuPSIG of the International Association for the Study of Pain.

Management of opioid side effects in cancer-related and chronic noncancer pain: a systematic review ☆

Side effects can limit opioid dosage and reduce quality of life. The purpose of this systematic review was to assess the management of opioid side effects in the context of cancer pain management or, in the event that no evidence was available for cancer pain, for chronic noncancer pain. The side effects studied were constipation, pruritus, nausea and vomiting, myoclonus, sedation, respiratory depression, and delirium. Opioid rotation to manage side effects was also studied. For each side effect, we searched MEDLINE and the Cochrane Controlled Trials Register and identified 657 possible titles for inclusion. Of these, 67 studies met inclusion criteria for analysis. The lack of well-designed, randomized controlled trials and the heterogeneity of populations and study designs made the drawing of firm conclusions difficult and precluded performance of meta-analysis. The type, strength, and consistency of evidence for available interventions to manage opioid side effects vary from strong (eg, on the use of naloxone to reverse respiratory depression or constipation) to weak (eg, changing from the oral to epidural route of morphine administration to manage sedation). Well-designed trials in the specified populations are required to furnish clinicians with secure evidence on managing opioid side effects successfully.

Single-dose intravenous paracetamol or propacetamol for prevention or treatment of postoperative pain: a systematic review and meta-analysis

Paracetamol is the most commonly prescribed analgesic for the treatment of acute pain. The efficacy and safety of i.v. formulations of paracetamol is unclear. We performed a systematic search (multiple databases, bibliographies, any language, to May 2010) for single-dose, randomized, controlled clinical trials of propacetamol or i.v. paracetamol for acute postoperative pain in adults or children. Thirty-six studies involving 3896 patients were included. For the primary outcome, 37% of patients (240/367) receiving propacetamol or i.v. paracetamol experienced at least 50% pain relief over 4 h compared with 16% (68/527) receiving placebo (number needed to treat=4.0; 95% confidence interval, 3.5-4.8). The proportion of patients in propacetamol or i.v. paracetamol groups experiencing at least 50% pain relief diminished over 6 h. Patients receiving propacetamol or paracetamol required 30% less opioid over 4 h and 16% less opioid over 6 h than those receiving placebo. However, this did not translate to a reduction in opioid-induced adverse events (AEs). Similar comparisons between propacetamol or i.v. paracetamol and active comparators were either not statistically significant, not clinically significant, or both. AEs occurred at similar rates with propacetamol or i.v. paracetamol and placebo. However, pain on infusion occurred more frequently in those receiving propacetamol compared with placebo (23% vs 1%). A single dose of either propacetamol or i.v. paracetamol provides around 4 h of effective analgesia for about 37% of patients with acute postoperative pain. Both formulations are associated with few AEs, although patients receiving propacetamol have a higher incidence of pain on infusion.

Nonsteroidal Anti-Inflammatory Drugs, Alone or Combined With Opioids, for Cancer Pain A Systematic Review

PURPOSE To assess the safety and efficacy of nonsteroidal anti-inflammatory drugs (NSAIDs), alone or combined with opioids, for the treatment of cancer pain. PATIENTS AND METHODS Forty-two trials involving 3,084 patients met inclusion criteria: eight compared NSAID with placebo; 13 compared one NSAID with another; 23 compared NSAID with opioid, NSAID or opioid versus NSAID plus opioid combinations, or NSAID plus opioid combinations versus NSAID plus opioid combinations; and nine studies assessed the effect of increasing NSAID dose. RESULTS Sixteen studies lasted 1 week or longer and 11 evaluated a single dose. Seven of eight trials demonstrated superior efficacy of single doses of NSAID compared with placebo. Only four of 13 studies reported increased efficacy of one NSAID compared with another; four other studies found that one NSAID had fewer side effects than one or more others. Thirteen of 14 studies found no difference, or minimal clinical difference, when comparing an NSAID plus opioid combination versus either drug alone. Comparisons between various NSAID plus opioid combinations were inconclusive. Four studies demonstrated increased efficacy with increased NSAID dose, without dose-dependent increases in side effects. CONCLUSION Heterogeneity of study methods and outcomes precluded meta-analyses. Short duration of studies undermines generalization of findings on efficacy and safety. On the basis of limited data, NSAIDs appear to be more effective than placebo for cancer pain; clear evidence to support superior safety or efficacy of one NSAID compared with another is lacking; and trials of combinations of an NSAID with an opioid have disclosed either no significant difference, or at most a slight but statistically significant advantage, compared with either single entity.

Efficacy of mu‐opioid agonists in the treatment of evoked neuropathic pain: Systematic review of randomized controlled trials

Several reviews of randomized controlled trials (RCTs) have shown the efficacy of mu‐opioids in reducing spontaneous neuropathic pain (NP). However, relatively little is known about their specific efficacy for evoked pain, which is a significant problem for many patients with NP. The present systematic review assesses the efficacy of opioid agonists for the treatment of evoked NP based upon published RCTs. We searched articles in any language using the MEDLINE database (1966 to December 2004), the Cochrane Central Register of Controlled Trials (4th quarter, 2004) and the reference lists of retrieved papers, employing search terms for RCTs, opioids and NP. Only RCTs in which opioid agonists were given to treat NP of any etiology, and evoked pain was assessed were included. Data were extracted by two independent investigators. Nine articles met inclusion criteria and were classified as short‐term (less than 24 h; n = 7) or intermediate‐term trials (4 weeks; n = 2). Although the scarcity of retrieved data precluded formal meta‐analysis of short‐term trials, we found that the intensity of dynamic mechanical allodynia was significantly attenuated by opioids relative to placebo in all studies. In contrast, no consistent effects on the magnitude of static allodynia, the threshold for mechanical allodynia or the threshold or magnitude of heat allodynia were found. The threshold and magnitude of cold‐induced allodynia generally responded positively to opioid treatments in patients with peripheral pain syndromes, but not central pain syndromes. Evoked pain was studied in only two intermediate‐term trials, in both of which oxycodone was significantly superior to placebo. The results of the two trials were combinable for a meta‐analysis that showed an overall 24 points difference in endpoint pain intensities between patients given opioids and those treated with placebo (95% CI −33 to −15; p < 0.00001). In conclusion: short‐term studies show that opioids can reduce the intensity of dynamic mechanical allodynia and perhaps of cold allodynia in peripheral NP. Insufficient evidence precludes drawing conclusions regarding the effect of opioids on other forms of evoked NP. A meta‐analysis of intermediate‐term studies demonstrates the efficacy of opioids over placebo for evoked NP. These findings are clinically relevant because dynamic mechanical allodynia and cold allodynia are the most prevalent types of evoked pain in NP.

A systematic review and meta-analysis of ketamine for the prevention of persistent post-surgical pain

While post‐operative pain routinely resolves, persistent post‐surgical pain (PPSP) is common in certain surgeries; it causes disability, lowers quality of life and has economic consequences. The objectives of this systematic review and meta‐analysis were to evaluate the effectiveness of ketamine in reducing the prevalence and severity of PPSP and to assess safety associated with its use.

Analgesic Efficacy and Safety of Morphine‐Chitosan Nasal Solution in Patients with Moderate to Severe Pain Following Orthopedic Surgery

INTRODUCTION Parenteral opioids are the standard of care for treating moderate to severe postsurgical pain. This randomized, double-blind, dose-ranging study compared the safety and efficacy of intranasal (IN) morphine with intravenous (IV) morphine and placebo. METHODS In total, 187 postbunionectomy patients with moderate to severe pain were randomized to receive IN morphine 3.75 mg, 7.5 mg, 15 mg, or 30 mg, IV morphine 7.5 mg, or placebo in the single-dose phase and IN morphine 7.5 mg or 15 mg thereafter. The primary outcome was a dose-response assessment for total pain relief based upon visual analog scales. Secondary endpoints included pain intensity, pain relief, patient global evaluation, and time to rescue medication. Safety assessments included adverse events and nasal examination. RESULTS A statistically significant linear dose response was observed over the IN morphine dose range for 4-hour total pain relief. Patients reported statistically significant pain relief and pain intensity differences following IV morphine and IN morphine at doses of 7.5 mg and greater within 30 minutes postdose, compared with placebo. Median times to rescue medication were 124 and 140 minutes for IN morphine 7.5 mg and 15 mg dosage groups, respectively, and 130 minutes for IV morphine. Local adverse events associated with IN morphine were transient and mostly mild (bad taste, nasal congestion, throat irritation, and sneezing). Systemic adverse events, regardless of route of administration, were dose-related and consistent with expected opioid effects. CONCLUSIONS By multiple measures of pain intensity and pain relief, IN morphine provides sustained analgesia in postsurgical patients and thus may offer a safe and less invasive alternative to IV morphine.

The Analgesic Efficacy and Safety of a Novel Intranasal Morphine Formulation (morphine plus Chitosan), Immediate Release Oral Morphine, Intravenous Morphine, and Placebo in a Postsurgical Dental Pain Model

BACKGROUND:Opioids are standard treatment for postoperative pain. In this study, we compared the safety and efficacy of intranasal (IN) morphine to IV and oral morphine and placebo. METHODS:Two-hundred-twenty-five patients with moderate-to-severe pain after third molar extraction were randomized to receive a single dose of IN morphine 7.5 mg or 15 mg, IV morphine 7.5 mg, oral morphine 60 mg or placebo. Pain intensity was assessed using visual analog and categorical scales, and pain relief using a categorical scale. Outcomes included total pain relief, pain intensity difference, summed pain intensity difference, time to analgesic onset, time to requesting rescue medication, and patients’ global evaluation of their treatment. Safety assessments included adverse event recording and nasal examinations. RESULTS:Across the various efficacy outcomes, both IN morphine doses were statistically similar to the positive comparators (IV and oral morphine), and all four morphine treatments were statistically superior to placebo. Overall, IN morphine 15 mg presented an efficacy profile similar to IV morphine 7.5 mg; both treatments demonstrated rapid onset of efficacy, generally persistent throughout the 6-h assessment period. The lower dose of IN morphine, 7.5 mg, was statistically similar to the other active treatments at 2 h and 6 h and similar to placebo at 4 h. Study medications were generally well tolerated, with no withdrawals due to adverse events or other safety concerns, and no serious adverse events reported. The most frequently reported adverse events were typical systemic opioid effects. CONCLUSIONS:IN morphine offers a noninvasive alternative to IV morphine for postoperative analgesia.

Platelet function following administration of a novel formulation of intravenous diclofenac sodium versus active comparators: a randomized, single dose, crossover study in healthy male volunteers.

STUDY OBJECTIVE To assess platelet function and safety following single-dose administration of a novel formulation of intravenous (IV) diclofenac sodium (Dyloject) 37.5 mg versus oral diclofenac 50 mg, IV ketorolac 30 mg, and oral acetylsalicylic acid (ASA) 325 mg. DESIGN Open-label, randomized, single-dose, 4-treatment crossover study. SETTING Clinical research unit. PATIENTS 30 healthy, ASA physical status I adult men. INTERVENTIONS Subjects were randomized to one of 6 treatment sequences that included 4 single-dose treatments. Study drug administration occurred on Days 1, 3, 5, and 7. MEASUREMENTS Platelet count, closure time as measured by platelet function analyzer (PFA-100), prothrombin time (PT), activated partial thromboplastin time (aPTT), and plasma concentrations of the study drugs were obtained over 24 hours after each treatment. The primary endpoint was the area under the curve for PFA collagen-epinephrine (CEPI) closure time difference from 0-6 hours post-drug administration (AUC(0-6h)). Secondary endpoints included the maximum change from baseline in PFA CEPI closure time. MAIN RESULTS AUC(0-6h) (mean ± SD) for CEPI closure time difference was significantly smaller after IV diclofenac 37.5 mg (249 ± 216 sec.hrs) than after ketorolac [and ASA (950 ± 287 sec.hrs and 834 ± 237 sec.hrs, respectively); P ≤ 0.0001 for both] but not after the oral diclofenac control (286 ± 265 sec.hrs; P = 0.40). Similarly, the maximum change from baseline in PFA CEPI closure time was lower after IV diclofenac than after ketorolac or ASA across all time intervals examined. There were no significant changes in PT or aPTT at any time point with any treatment. There was a low frequency of adverse events. CONCLUSIONS Acetylsalicylic acid and ketorolac both substantially disrupted platelet function in contrast to IV diclofenac 37.5 mg or oral diclofenac 50 mg control. Diclofenac, with its balanced COX-1 and COX-2 inhibitory profile, may pose less risk of postoperative bleeding than nonsteroidal antiinflammatory drugs (NSAIDs) such as ketorolac and ASA, which predominantly inhibit COX-1.