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Purpose CYP2D6 bioactivates codeine and tramadol, with intermediate and poor metabolizers (IMs and PMs) expected to have impaired analgesia. This pragmatic proof-of-concept trial tested the effects of CYP2D6-guided opioid prescribing on pain control. Methods Participants with chronic pain (94% on an opioid) from seven clinics were enrolled into CYP2D6-guided ( n  = 235) or usual care ( n  = 135) arms using a cluster design. CYP2D6 phenotypes were assigned based on genotype and CYP2D6 inhibitor use, with recommendations for opioid prescribing made in the CYP2D6-guided arm. Pain was assessed at baseline and 3 months using PROMIS ® measures. Results On stepwise multiple linear regression, the primary outcome of composite pain intensity (composite of current pain and worst and average pain in the past week) among IM/PMs initially prescribed tramadol/codeine ( n  = 45) had greater improvement in the CYP2D6-guided versus usual care arm (-1.01 ± 1.59 vs. -0.40 ± 1.20; adj P  = 0.016); 24% of CYP2D6-guided versus 0% of usual care participants reported ≥30% (clinically meaningful) reduction in the composite outcome. In contrast, among normal metabolizers prescribed tramadol or codeine at baseline, there was no difference in the change in composite pain intensity at 3 months between CYP2D6-guided (-0.61 ± 1.39) and usual care (-0.54 ± 1.69) groups (adj P  = 0.540). Conclusion These data support the potential benefits of CYP2D6-guided pain management.

PurposeEffect size estimates of analgesic drugs can be misleading. Ibuprofen (400 mg, 600 mg, 800 mg), paracetamol (1000 mg, 500 mg), paracetamol 1000 mg/codeine 60 mg, and placebo were investigated to establish the multidimensional pharmacodynamic profiles of each drug on acute pain with calculated effect size estimates.MethodsA randomized, double-blind, single-dose, placebo-controlled, parallel-group, single-centre, outpatient, and single-dose study used 350 patients (mean age 25 year, range 18 to 30 years) of homogenous ethnicity after third molar surgery. Primary outcome was sum pain intensity over 6 h. Secondary outcomes were time to analgesic onset, duration of analgesia, time to rescue drug intake, number of patients taking rescue drug, sum pain intensity difference, maximum pain intensity difference, time to maximum pain intensity difference, number needed to treat values, adverse effects, overall drug assessment as patient-reported outcome measure (PROM), and the effect size estimates NNT and NNTp.ResultsIbuprofen doses above 400 mg do not significantly increase analgesic effect. Paracetamol has a very flat analgesic dose–response profile. Paracetamol 1000/codeine 60 mg gives similar analgesia as ibuprofen from 400 mg, but has a shorter time to analgesic onset. Active drugs show no significant difference in maximal analgesic effect. Other secondary outcomes support these findings. The frequencies of adverse effects were low, mild to moderate in all active groups. NNT and NTTp values did not coincide well with PROMs.ConclusionIbuprofen doses above 400 mg for acute pain offer limited analgesic gain. Paracetamol 1000 mg/codeine 60 mg is comparable to ibuprofen doses from 400 mg. Calculated effect size estimates and PROM in our study seem not to relate well as clinical analgesic efficacy estimators.Trial registrationNCT00699114.

PurposeCombining analgesics with different mechanisms of action may increase the analgesic efficacy. The multidimensional pharmacodynamic profiles of ibuprofen 400 mg/paracetamol 1000 mg, ibuprofen 400 mg/paracetamol 1000 mg/codeine 60 mg, and paracetamol 1000 mg/codeine 60 mg and placebo were compared.MethodsA randomized, double-blind, placebo-controlled, parallel-group, single-centre, outpatient, and single-dose study used 200 patients of both sexes and homogenous ethnicity after third molar surgery (mean age 24 years, range 19–30 years). Primary outcome was sum pain intensity over 6 h (SPI). Secondary outcomes were time to analgesic onset, duration of analgesia, time to rescue drug intake, number of patients taking rescue drug, sum pain intensity difference (SPID), maximum pain intensity difference, time to maximum pain intensity difference, number needed to treat, prevent remedication and harm values, adverse effects, and patient-reported outcome measure (PROM).ResultsAnalgesia following ibuprofen and paracetamol combination with or without codeine was comparable. Both were better than paracetamol combined with codeine. Secondary variables supported this finding. Post hoc analysis of SPI and SPID revealed a sex/drug interaction trend in the codeine-containing groups where females experienced less analgesia. PROM showed a significant sex/drug interaction in the paracetamol and codeine group, but not in the other codeine-containing group. Especially females reported known and mild side effects in the codeine-containing groups.ConclusionCodeine added to ibuprofen/paracetamol does not seem to add analgesia in a sex-mixed study population. Sex may be a confounding factor when testing weak opioid analgesics such as codeine. PROM seems to be more sensitive than traditional outcome measures.Trial registrationClinicalTrials.gov June 2009 NCT00921700.

Objective To compare the analgesic efficacy and side effects of the synthetic cannabinoid nabilone with those of the weak opioid dihydrocodeine for chronic neuropathic pain. Design Randomised, double blind, crossover trial of 14 weeks’ duration comparing dihydrocodeine and nabilone.Setting Outpatient units of three hospitals in the United Kingdom.Participants 96 patients with chronic neuropathic pain, aged 23-84 years. Main outcome measures The primary outcome was difference between nabilone and dihydrocodeine in pain, as measured by the mean visual analogue score computed over the last 2 weeks of each treatment period. Secondary outcomes were changes in mood, quality of life, sleep, and psychometric function. Side effects were measured by a questionnaire.Intervention Patients received a maximum daily dose of 240 mg dihydrocodeine or 2 mg nabilone at the end of each escalating treatment period of 6 weeks. Treatment periods were separated by a 2 week washout period.Results Mean baseline visual analogue score was 69.6 mm (range 29.4-95.2) on a 0-100 mm scale. 73 patients were included in the available case analysis and 64 patients in the per protocol analysis. The mean score was 6.0 mm longer for nabilone than for dihydrocodeine (95% confidence interval 1.4 to 10.5) in the available case analysis and 5.6 mm (10.3 to 0.8) in the per protocol analysis. Side effects were more frequent with nabilone.Conclusion Dihydrocodeine provided better pain relief than the synthetic cannabinoid nabilone and had slightly fewer side effects, although no major adverse events occurred for either drug. Trial registration Current Controlled Trials ISRCTN15330757.

Abstract Objective To assess CYP2D6 genotype prevalence in chronic pain patients treated with tramadol or codeine. Design Prospective cohort study. Setting General hospital, pain management unit. Subjects Patients with chronic pain, treated with codeine or tramadol. Methods Patients’ pain was assessed at baseline (numeric rating scale [NRS]; 0–10). Prescription of codeine or tramadol was selected randomly. The assessment of patients’ response to the drug in terms of pain relief and adverse effects was performed after 24 hours. Reduction of pain intensity of >50% or an NRS <4 was considered a positive response. Patients’ blood samples were collected during the first visit. Genotyping for the common variants CYP2D6 *2, *3, *4, *5, *6, *9, *10, *14, and *17 was performed, and alleles not carrying any polymorphic allele were classified as CYP2D6*1 (wild-type [wt]). Results Seventy-six consecutive patients were studied (20 males, 56 females), aged 21–85 years. Thirty-four received tramadol and 42 codeine. The main genotypes of CYP2D6 identified were the wt/wt (35.5%), the *4/wt (17.1%), and the *6/wt (10.5%). Adverse effects were common, especially in carriers of *9/*9, *5/*5, *5/*4, and *10/*10, as well as in variants including the 4 allele (*4/*1 [38.4%] and *4/*4 [42.8%]). Conclusions Genotyping can facilitate personalized pain management with opioids, as specific alleles are related to decreased efficacy and adverse effects.

Purpose To assess the analgesia and side effects of codeine phosphate associated with paracetamol (test medication) as compared to paracetamol (control medication) after the extraction of impacted mandibular third molars. Materials and methods Forty-seven patients removed the right and left impacted mandibular third molars. After one surgery, patients took the test medication and after the other surgery, they took the control medication. Patients with exacerbated pain were prescribed to use the rescue medication instead of the medication initially administered and were included in the rescue group. They were evaluated for 7 days postoperatively, and the mean score of the visual analogue scale (VAS) of pain between test and control medications was assessed by the Poisson distribution. The side effects of these medications were assessed by the patient’s complaints. A P value of < .05 was considered to be statistically significant. Results The mean score of the VAS of pain was not statistically different between test and control medications in the non-rescue group, but it was significantly greater in patients previously using paracetamol in the rescue group. The most common side effects reported in both groups, predominantly in patients using the test medication, were drowsiness, dizziness, and nausea. Conclusion The use of codeine phosphate associated with paracetamol after the extraction of impacted mandibular third molars is a better choice to control the postoperative pain rather than paracetamol, but with more side effects, which are clinically acceptable.

Aspirin is a widely used NSAID that has been extensively studied in numerous conditions. Nonprescription analgesics, such as aspirin, are frequently used for a wide variety of common ailments, including conditions such as dental pain and tension-type headache. We sought to compare the efficacy and safety profiles of aspirin, acetaminophen with codeine, and placebo in the treatment of post-operative dental pain and tension-type headache. These were 2 randomized, double-blind, placebo-controlled, single-dose clinical trials that assigned participants (2:2:1) to receive either aspirin (1000 mg), acetaminophen (300 mg) with codeine (30 mg), or placebo. The primary efficacy end point was the sum of pain intensity differences from baseline (SPID) over 6 hours for the dental pain study and over 4 hours for the tension-type headache study. Other common analgesic measures, in addition to safety, were also evaluated. The results of the dental pain study for aspirin and acetaminophen with codeine suggest statistically significant efficacy for all measures compared with placebo at all time points. Aspirin provided statistically significant efficacy compared with acetaminophen with codeine for SPID0–4 (P = 0.028). In the tension-type headache study, aspirin and acetaminophen with codeine provided statistically significant efficacy compared with placebo for SPID0–4 and SPID0–6 (P < 0.001) and for total pain relief (P < 0.001). There were no significant differences between aspirin and acetaminophen with codeine at any evaluation of SPID (P ≥ 0.070), complete relief (P ≥ 0.179), or time to meaningful relief (P ≥ 0.245). Regarding safety, there were no statistically significant differences between treatment groups in the incidence of adverse events in the dental pain and tension-type headache studies. These 2 randomized, double-blind, placebo-controlled studies demonstrate that treatment with aspirin (1000 mg) provides statistically significant analgesic efficacy compared with placebo use and comparable efficacy with acetaminophen (300 mg) with codeine (30 mg) therapy after impacted third molar extraction and in tension- type headache.

Analgesics are an essential component of the treatment of cancer-associated pain. Pharmacologic treatment is usually begun with nonopioid analgesics, most frequently acetaminophen. If pain relief is not achieved, the so-called “weak” opioids, such as codeine and hydrocodone, may be used in combination with acetaminophen. Adverse effects (AEs) of the opioids include constipation, somnolence, nausea, and vomiting. Based on the results of a literature search, data comparing the effects of the opioids are lacking. The purpose of this study was to compare the analgesic efficacy and tolerability of codeine phosphate versus hydrocodone bitartrate in combination with acetaminophen in the relief of cancer-related pain. This 23-day, prospective, double-blind, randomized, parallel-group study was conducted at 3 Colombian centers: University Libre, Social Security Institute, and General Hospital of Medellín, Cali, Colombia. Outpatients with cancer were eligible for the study if they were aged >-18 years and had chronic (duration, ≥ 3 months) moderate to severe cancer-related pain (score on 10-cm visual analog scale [VAS], > 3 cm [moderate]; score on a 4-point verbal pain-intensity scale, > 1 [moderate]). Eligible patients were randomly assigned to receive 1 tablet of codeine/acetaminophen (C/A) 30/500 mg or hydrocodone/acetaminophen (H/A) 5/500 mg PO q4h (total daily doses, 150/2500 and 25/2500 mg, respectively) for 23 days. In both groups, if pain intensity was rated as > 3 on the VAS at week 1 or 2, the dosage was doubled. The primary end point was the proportion of patients who achieved pain relief (defined as a score of > 1 on a 5-point verbal rating scale [VRS] (0 = none; 1 = a little; 2 = some; 3 = a lot; and 4 = complete) on study days 1 and 2 and weeks 1, 2, and 3. The secondary end point was the proportion of patients in whom pain was decreased (VAS score, <- 3 cm). AEs were self-reported on a 4-point VRS (0 = absent; 1 = mild; 2 = moderate; and 3 = severe). Of the 121 patients who participated, 59 received C/A and 62 received H/A. Of the total number of cases, 59% were aged 60 to 89 years, and 55% were men. At baseline, 88% of the patients described their pain intensity as moderate; 12%, severe. Of the patients who received C/A, 58% responded to the initial dosage of 150/2500 mg/d, and 8% of the patients responded to the double dosage; 34% did not experience pain relief. In patients with H/A, pain was reported as absent or mild in 56% of patients at the starting dosage of 25/2500 mg/d; an additional 15% of the patients responded to the double dosage; the remaining 29% of patients did not experience any pain relief. None of the between-group differences in response rates were significant. The most common AEs in the C/A and H/A groups were constipation (36% and 29%, respectively), dizziness (24% and 19%), vomiting (24% and 16%), and dry mouth (15% and 18%), with no significant differences between groups. In this study, efficacy and tolerability were comparable between C/A and H/A over 23 days of treatment in these patients with moderate or severe, chronic, cancer-related pain.

Background In this study, we compared the quality of transitional analgesia provided by bilateral superficial cervical plexus block (SCPB) or morphine following a remifentanil-based anesthesia for infratentorial or occipital craniotomy. Methods In this randomized controlled and double-blind study, 30 patients scheduled for infratentorial or occipital craniotomy were divided randomly into two groups: group morphine (morphine 0.1 mg·kg −1 iv after dural closure and a SCPB performed with 20 mL of 0.9% saline at the end of the surgery) or group block (10 mL of 0.9% saline iv instead of morphine after dural closure and a SCPB performed with 20 mL of a 1:1 mixture of 0.5% bupivacaine and 2% lidocaine at the end of the surgery). Postoperative pain was assessed at one, two, four, eight, 12, 16, and 24 hr using an 11-point (0-10) numerical rating scale (NRS). Analgesia was provided with subcutaneous codeine. Results Average NRS scores were similar between the two groups at each time interval over the study period. The average scores (with 95% confidence interval) were 3.9 (3.4-4.4) and 4.3 (3.8-4.9) for the block and morphine groups, respectively ( P = 0.25). The delay before administration of the first dose of codeine was not statistically different between the two groups: 25 min (5-2,880) vs 21.5 min (5-90), median and range for the block and morphine groups, respectively. The incidence of nausea and vomiting was similar between the two groups. Conclusion Bilateral superficial cervical plexus block provides transitional analgesia that is clinically equivalent to morphine following remifentanil-based anesthesia in patients undergoing occipital or infratentorial craniotomies.

Key Points This paper reviews the available high quality information on analgesics commonly prescribed by dentists, including COX-2 selective inhibitors. Problems related to chance effects are avoided by combining multiple trials in a meta-analysis. There is good evidence of efficacy for most commonly-prescribed analgesics. Standard doses of NSAIDs and COX-2 inhibitors provide the best analgesia and lowest rate of adverse events. Objectives To compare the relative efficacy of analgesics after third molar extraction from systematic reviews of randomised, double blind studies. Data sources Dental trials from systematic reviews of randomised, double-blind studies of analgesics in acute pain. Data selection Number of patients with moderate or severe pain achieving at least half pain relief over 4 to 6 hours after a single oral dose of analgesic. Data extraction Independently by two reviewers. Data synthesis Use of dichotomous information from active and placebo treatments, first to calculate the statistical significance using relative risk, and then to evaluate the clinical relevance using number needed to treat (NNT). Non-steroidal anti-inflammatory drugs (NSAIDs) and cyclo-oxygenase-2 (COX-2) inhibitors had the lowest (best) NNTs for the outcome of at least half pain relief over 4-6 hours compared with placebo. With the best performing analgesics, 50-70 patients out of 100 had good pain relief compared with about 10 out of 100 with placebo. Only paracetamol 600/650 mg plus codeine 60 mg was associated with any significant increase in any patient experiencing an adverse event. Conclusions NSAIDs and COX-2 inhibitors have the lowest (best) NNTs. They may also have fewer adverse effects after third molar surgery, though conclusive evidence is lacking. At least 80% of analgesic prescribing by UK dentists is in line with the best available evidence on efficacy and safety.