Oral cannabidiol (CBD) as add-on to paracetamol for painful chronic osteoarthritis of the knee: a randomized, double-blind, placebo-controlled clinical trial.

Background: Painful knee osteoarthritis (KOA) is common, pharmacological treatment, however, is often hampered by limited tolerability. Cannabidiol, which preclinically showed anti-inflammatory, analgesic activity, could supplement established analgesics, but robust clinical trials are lacking. The aim of our study was to investigate the effects of oral high-dose CBD administered over 8 weeks on pain, function and patient global assessment as an add-on to continued paracetamol in chronic symptomatic KOA. Methods: Prospective, randomized, placebo-controlled, double-blind, parallel-group study. Single center, Outpatient Clinic, Department of Special Anaesthesia and Pain Therapy at Medical University of Vienna, Austria. Eligibility criteria included: age: 18-98 years; painful KOA; score ≥5 on the pain subscale of the Western Ontario and McMasters Universities Osteoarthritis (WOMAC) Index; KOA confirmed by imaging. Participants were on continued dosage of paracetamol 3 g/d and randomly assigned by web-based software 1:1 to oral cannabidiol 600 mg/d (n = 43) or placebo (n = 43). Study period: 8 weeks. Primary outcome: Change in WOMAC pain subscale scores (0 = no pain, 10 = worst possible pain) from baseline to week 8 of treatment. Trial Registration: ClinicalTrials.gov Identifier: NCT04607603. Trial is completed. Findings: The trial was conducted from October 1, 2020 to March 29, 2022. 159 patients screened, 86 randomized. Among 86 participants (mean age, 62.8 [SD 20.3] years; 60 females [69.8%]), 58 (67.4%) completed the trial. Mean baseline WOMAC pain subscale was 6.0 ± 1.1. Analysis: Intention-to-treat principal. Mean reduction in WOMAC pain subscale was 2.5 (95% CI: 1.8-3.3) in the cannabidiol group and 2.4 (95% CI: 1.7-3.2) in the placebo group with no significant group difference (p = 0.80). Adverse events were significantly more frequent with cannabidiol (cannabidiol: 135 [56%]; placebo: 105 [44%]) (p = 0.008). Rise above baseline of liver aminotransferases and gamma-glutamyltransferase was significantly more common in the cannabidiol (n = 15) than the placebo group (n = 5) (p = 0.02). Interpretation: In KOA patients, oral high-dose add-on cannabidiol had no additional analgesic effect compared to adding placebo to continued paracetamol. Our results do not support the use of cannabidiol as an analgesic supplement in KOA. Funding: Trigal Pharma GmbH.

Tapentadol in the management of cancer pain: current evidence and future perspectives.

Thanks to the progress in early diagnosis and treatment of cancer, the life expectancy of cancer patients has now increased. Patients are, therefore, more likely to experience their individual cancer pain as a chronic pain. As a consequence, long-term treatment of cancer-related pain and oncological therapy-related pain are a major need for all patients and a challenge to all healthcare professionals. Tapentadol is a centrally acting analgesic drug characterized by two synergistic mechanisms of action, since it acts at the µ-opioid receptor (MOR) and inhibits noradrenalin re-uptake (NRI). Therefore, tapentadol has been considered the first of a new class of drugs, MOR-NRI. Tapentadol has been tested in different populations of cancer patients (opioid-naive and -pretreated), such as those with pain of mixed etiology, patients with pain from hematological malignancies and patients experiencing pain conditions due to anticancer treatment. According to available evidence, tapentadol prolonged release was well tolerated and effective in cancer pain patients. In randomized, double-blind and active-controlled trials it proved non-inferior to standard opioids like morphine or oxycodone in the management of moderate-to-severe cancer pain, both in opioid-naive and in opioid-pretreated patients. The good analgesic efficacy may be partly due to the action of tapentadol on neuropathic pain components. Together with the low rate of gastrointestinal adverse effects and the overall favorable safety profile, tapentadol can be considered a good option in cancer pain patients, who can suffer frequently from nausea, vomiting, constipation or other events that further reduce their quality of life.

Tapentadol for neuropathic pain: a review of clinical studies.

Neuropathic pain (NP) is an enormous burden for patients, caregivers and society. NP is a pain state that may develop after injury of the peripheral or central nervous system because of a wide range of diseases and traumas. A NP symptom component can be found also in several types of chronic pain. Many NP patients are substantially disabled for years. Due to its chronicity, severity and unpredictability, NP is difficult to treat. Tapentadol is a central-acting oral analgesic with combined opioid and noradrenergic properties, which make it potentially suitable for a wide range of pain conditions, particularly whenever a NP component is present or cannot be excluded. In randomized controlled trials, tapentadol has proved to be effective in relieving NP in diabetic peripheral neuropathy and in chronic low back pain. In observational studies, tapentadol reduced NP in chemotherapy-induced peripheral neuropathies, blood and solid cancers, and the NP component in neck pain and Parkinson's disease. This narrative review aims to provide clinicians with a broad overview of tapentadol effects on NP.

Opioids for chronic non-cancer pain: a critical view from the other side of the pond.

Opioid analgesics are important therapeutic options for chronic non-cancer pain (CNCP), recognized as a major public health issue with high social and economic burden. The increasing therapeutic opioid use for CNCP, misuse and abuse of prescription opioids have become matters of severe concern in USA. The recent position paper of the American Academy of Neurology (AAN) about the use of opioids in USA expresses growing alarms about opioid misuse/abuse, and has alerted physicians worldwide to rethink about their prescription practice. Current US practice in opioid prescription has been associated with morbidity and mortality of epidemic proportions: over 100,000 people directly or indirectly died from prescribed opioids in USA in the last twenty years, reaching 16,651 deaths in 2010. The actually alarming data from US have initiated pain physicians and researchers to re-evaluate their prescribing policies and attitudes for long-term treatment of non-cancer patients with opioids. In this position paper it is explained that any change in clinical behavior should not be based on an uncritical generalization of the US data that do not reflect the European situation. The primary objective of pain physicians remains to adequately treat chronic pain. Opioids are and will continue to remain an essential part of the "armamentarium against pain"; physicians should use them in the best way, i.e. after thorough diagnosis, assessment of alternative therapeutic options in the context of a multimodal treatment concept, and with repeated careful re-evaluations of the proper indication by a close long-term follow-up of any chronic opioid patient.

Current pain education within undergraduate medical studies across Europe: Advancing the Provision of Pain Education and Learning (APPEAL) study.

OBJECTIVES: Unrelieved pain is a substantial public health concern necessitating improvements in medical education. The Advancing the Provision of Pain Education and Learning (APPEAL) study aimed to determine current levels and methods of undergraduate pain medicine education in Europe. DESIGN AND METHODS: Using a cross-sectional design, publicly available curriculum information was sought from all medical schools in 15 representative European countries in 2012-2013. Descriptive analyses were performed on: the provision of pain teaching in dedicated pain modules, other modules or within the broader curriculum; whether pain teaching was compulsory or elective; the number of hours/credits spent teaching pain; pain topics; and teaching and assessment methods. RESULTS: Curriculum elements were publicly available from 242 of 249 identified schools (97%). In 55% (133/242) of schools, pain was taught only within compulsory non-pain-specific modules. The next most common approaches were for pain teaching to be provided wholly or in part via a dedicated pain module (74/242; 31%) or via a vertical or integrated approach to teaching through the broader curriculum, rather than within any specific module (17/242; 7%). The curricula of 17/242 schools (7%) showed no evidence of any pain teaching. Dedicated pain modules were most common in France (27/31 schools; 87%). Excluding France, only 22% (47/211 schools) provided a dedicated pain module and in only 9% (18/211) was this compulsory. Overall, the median number of hours spent teaching pain was 12.0 (range 4-56.0 h; IQR: 12.0) for compulsory dedicated pain modules and 9.0 (range 1.0-60.0 h; IQR: 10.5) for other compulsory (non-pain specific) modules. Pain medicine was principally taught in classrooms and assessed by conventional examinations. There was substantial international variation throughout. CONCLUSIONS: Documented pain teaching in many European medical schools falls far short of what might be expected given the prevalence and public health burden of pain.

Improved patient functioning after treatment of breakthrough cancer pain: an open-label study of fentanyl buccal tablet in patients with cancer pain.

PURPOSE: This open-label study evaluated the effects of fentanyl buccal tablet (FBT) on functioning and mood in cancer patients with breakthrough cancer pain (BTcP). METHODS: Opioid-tolerant patients in seven European countries with up to four BTcP episodes/day received FBT doses (100-800 µg) identified during open-label titration to treat up to eight BTcP episodes during an open-label treatment period. In countries where FBT was not commercially available, patients could enter an open-label continuation phase. Functionality and satisfaction assessments included change from baseline to the end of the treatment period in the modified Brief Pain Inventory (BPI-7S) seven-item interference subscale, patient's global assessment of satisfaction and ease of use, and Patient's Global Impression of Change (PGIC). Safety was also assessed. RESULTS: Of 330 randomized patients, 218 completed the treatment period and 88 entered the continuation phase. Median background pain intensity was 4.0 (mild) throughout the study. After the treatment period, mean (SD) global modified BPI-7S score improved from 39.7 (15.9) at baseline to 31.6 (16.8) for a mean change of -8.6 (95% confidence interval CI -10.5, -6.7; P < 0.0001), and 74.5% of patients reported improvement in overall status (PGIC) compared with 25.5% who reported no change or worsening (P < 0.001). Treatment-related adverse events (≥2 patients) during the continuation phase were application site erythema (6.9%), application site swelling (4.6%), and vertigo (4.6%). CONCLUSIONS: FBT may improve patient functioning, mood, and overall satisfaction in the management of BTcP. Long-term data did not indicate new safety concerns with FBT doses up to 800 µg.

Tapentadol prolonged release for managing moderate to severe, chronic malignant tumor-related pain.

BACKGROUND: Tapentadol prolonged release (PR) is effective and well tolerated for chronic osteoarthritis, low back, and diabetic peripheral neuropathic pain. OBJECTIVES: To evaluate the efficacy and tolerability of tapentadol PR compared with placebo and morphine controlled release (CR) for managing moderate to severe chronic malignant tumor-related pain. STUDY DESIGN: Randomized-withdrawal, parallel group, active- and placebo-controlled, double-blind phase 3 study (NCT00472303). SETTING: Primary, secondary, and tertiary care settings in 16 countries. METHODS: Eligible patients (pain intensity ≥ 5 [11-point numerical rating scale] on prior analgesics) were randomized (2:1) and titrated to their optimal dose of tapentadol PR (100-250 mg bid) or morphine sulfate CR (40-100 mg bid) over 2 weeks. Morphine sulfate immediate release 10 mg was permitted as needed for rescue medication (no maximum dose). Patients who completed titration and, during the last 3 days of titration, had mean pain intensity < 5 (based on twice-daily ratings) and mean rescue medication use = 20 mg/day continued into a 4-week maintenance period; patients who received morphine CR during titration continued taking morphine CR, and those who received tapentadol PR were re-randomized (1:1) to tapentadol PR or placebo bid. Response during maintenance (primary efficacy endpoint) was defined as having: (1) completed the maintenance period, (2) a mean pain intensity < 5 during maintenance, and (3) used an average of = 20 mg/day of rescue medication during maintenance. Response at the end of titration was defined similarly, with pain intensity and rescue medication averages based on the last 3 days of titration. RESULTS: Of 622 patients screened, 496 were randomized, treated during titration, and evaluable for safety; 327 were re-randomized, treated during maintenance, and evaluable for safety; and 325 were evaluable for efficacy. The adjusted responder rate estimate during maintenance (logistic regression adjusting for treatment group, pooled center, and pain intensity at start of maintenance) was significantly higher with tapentadol PR (64.3%) than with placebo (47.1%; odds ratio (OR), 2.02 [95% confidence interval (CI), 1.12 - 3.65]; P = 0.02). Based on responder rates at the end of titration, tapentadol PR (76.0% [174/229]) was non-inferior to morphine CR (83.0% [83/100]). The lower limit of the 95% CI for the between-groups difference (-15.5%) was within the pre-specified 20% non-inferiority margin. During titration, incidences of treatment-emergent adverse events (TEAEs) were 50.0% (169/338) with tapentadol PR and 63.9% (101/158) with morphine CR; incidences of nausea, vomiting, and dry mouth were lower with tapentadol PR than with morphine CR. During maintenance, incidences of TEAEs were 56.3% (63/112), 62.3% (66/106), and 62.4% (68/109) with placebo, tapentadol PR, and morphine CR, respectively. LIMITATIONS: Statistical comparisons between tapentadol PR and morphine CR were limited to descriptive statistics during the maintenance period because of the pre-selection of responders to tapentadol PR or morphine CR during titration. CONCLUSIONS: Results obtained during maintenance indicate that tapentadol PR (100-250 mg bid) is effective compared with placebo for managing moderate to severe chronic malignant tumor-related pain. Based on results obtained during titration, tapentadol PR provides comparable efficacy to that of morphine sulfate CR (40-100 mg bid), but is associated with better gastrointestinal tolerability.

The importance of putting pain on the curricula in medical schools in Europe.

Pain continues to be underdiagnosed and undertreated in Europe. A lack of training in pain medicine among clinicians has been identified as a barrier to optimal pain management. Except for clinicians entering specialized training in pain medicine or a related field, inadequate or nonexistent pain management training is the norm in Europe. A multidisciplinary group of experts, including representatives from the European Federation of IASP (International Association for the Study of Pain) Chapters (EFIC), is launching a pan-European initiative aimed at raising the profile and importance of undergraduate pain education.

Effectiveness and safety of tapentadol prolonged release for severe, chronic low back pain with or without a neuropathic pain component: results of an open-label, phase 3b study.

OBJECTIVE: This open-label, phase 3b study evaluated the effectiveness and tolerability of tapentadol prolonged release and tapentadol immediate release (for acute pain episodes) for severe, chronic low back pain with or without a neuropathic pain component that was inadequately managed in patients taking World Health Organization (WHO) Step I or II analgesics or who were not regularly treated with analgesics. RESEARCH DESIGN AND METHODS: Average baseline pain intensity was greater than 5 (11-point numerical rating scale-3 [NRS-3; 3-day average pain intensity]) with WHO Step I or II analgesics and greater than 6 with no regular analgesic regimen. WHO Step II analgesics were discontinued before starting study treatment; WHO Step I analgesics or co-analgesics were continued at the same dose. Patients received tapentadol prolonged release (50-250 mg bid) during a 5-week titration and 7-week maintenance period. Tapentadol immediate release was permitted for acute pain episodes (tapentadol prolonged release and immediate release maximum combined dose, ≤500 mg/day). The painDETECT questionnaire was used to define subsets of patients based on the probability of a neuropathic pain component to their low back pain as 'negative', 'unclear', or 'positive'. CLINICAL TRIAL REGISTRATION: NCT00983385. MAIN OUTCOME MEASURE: The primary endpoint was the change from baseline to week 6 in average pain intensity (NRS-3), using the last observation carried forward to impute missing scores. RESULTS: In the painDETECT negative (n = 49) and unclear/positive (n = 126) subsets, respectively, mean (SD) changes in pain intensity from baseline to week 6 were -2.4 (2.18) and -3.0 (2.07; both p < 0.0001). Among patients who had not received prior WHO Step II treatment, lower doses of tapentadol prolonged release were generally required with increasing likelihood of a neuropathic pain component. Based on the painDETECT questionnaire and the Neuropathic Pain Symptom Inventory (NPSI), tapentadol prolonged release treatment was also associated with significant improvements in neuropathic pain symptoms, with decreases in the number of pain attacks and the duration of spontaneous pain in the last 24 hours in patients with low back pain with a neuropathic pain component (painDETECT unclear or positive score at baseline or screening). The most common treatment-emergent adverse events (incidence ≥10%, n = 176) were nausea, dizziness, headache, dry mouth, fatigue, constipation, diarrhea, nasopharyngitis, and somnolence. CONCLUSIONS: Tapentadol prolonged release was well tolerated and effective for managing severe, chronic low back pain with or without a neuropathic pain component.

Novel double and single ryanodine receptor 1 variants in two Austrian malignant hyperthermia families.

BACKGROUND: Malignant hyperthermia (MH) is a potentially lethal genetic disorder in response to volatile anesthetics and depolarizing muscle relaxants. To support the claim that a novel genetic variant causes MH, it is necessary to demonstrate that it has significant effects on the sensitivity of the ryanodine receptor (RYR1) calcium channel. In this study we focused on 2 Austrian families with strong MH disposition and new RYR1 variants. METHODS: We sequenced the entire coding region of the RYR1 from 2 Austrian MH individuals. Genotype-phenotype segregation and evolutionary conservation of the variants were considered. On a functional level, Ca(2+) release experiments with fura-2-acetoxymethyl ester were performed in cultured skeletal muscle cells derived from individuals carrying the new variants and compared with control cells from nonsusceptible individuals. Caffeine, 4-chloro-m-cresole (4-CmC), and halothane were used as specific Ca(2+) releasing agents. RESULTS: The variant p.A612P in family A segregated with an MH-susceptible phenotype and cells showed an increased sensitivity for all Ca(2+)-releasing substances tested. In family B, 2 variants (p.R2458H/p.R3348C) were identified. While p.R2458H and p.R2458H/p.R3348C segregated with an MH-susceptible diagnosis, p.R3348C alone showed an MH equivocal diagnosis. Ca(2+)-release experiments showed that exchanges of these highly conserved amino acids increased the sensitivities for the substances tested (except 4-CmC with p.R2458H and p.R3348C) when compared with the MH-negative control group. CONCLUSIONS: Our results suggest that these variants are new causative MH variants.

Subcutaneous target stimulation (STS) in chronic noncancer pain: a nationwide retrospective study.

Stimulation of primary afferent neurons offers a new approach for the control of localized chronic pain. We describe the results with a new neurostimulation technique, subcutaneous target stimulation (STS), for the treatment of chronic focal noncancer pain. STS applies permanent electrical stimulation directly at the painful area via a percutaneous-placed subcutaneous lead. We reported the clinical outcomes of 111 patients with focal chronic, noncancer pain treated with STS in this first nationwide, multicenter retrospective analysis. The indications for STS were low back pain (n = 29) and failed back surgery syndrome (back pain with leg pain) (n = 37), cervical neck pain (n = 15), and postherpetic neuralgia (n = 12). Pain intensity was measured on a numerical rating scale (NRS) before and after implantation. Data on analgesic medication, stimulation systems, position, and type of leads and complications were obtained from the patients' records. After implantation, the mean pain intensity improved by more than 50% (mean NRS reduction from 8.2 to 4.0) in the entire patient group (P = 0.0009). This was accompanied by a sustained reduction in demand for analgesics. In all the patients, the STS leads were positioned directly at the site of maximum pain. Lead dislocation occurred in 14 patients (13%), infections in 7 (6%), and in 6 cases (5%), lead fractures were observed. The retrospective data analysis revealed that STS effectively provided pain relief in patients suffering from refractory focal chronic noncancer pain and that STS is an alternative treatment option. Prospective controlled studies are required to confirm these retrospective findings. This article presents a new minimally invasive technique for therapy-resistant focal pain.

Transdermal fentanyl matrix patches Matrifen and Durogesic DTrans are bioequivalent.

AIM: The pharmacokinetic profiles of the two commercially available transdermal fentanyl patches Matrifen (100 microg/h) and Durogesic DTrans (100 microg/h), used to manage severe chronic pain, were compared regarding their systemic exposure, rate of absorption, and safety. METHODS: Transdermal matrix fentanyl patches [Matrifen or Durogesic DTrans (100 microg/h)] were applied for 72 h to 30 healthy male subjects in a randomized, four-period (two replicated treatment sequences), crossover study; 28 subjects completed the study. The pharmacokinetic parameters of fentanyl were determined for 144 h after application using plasma samples. Safety of the patches (adverse events) and performance (adhesion, skin irritation, residual fentanyl content in the patch) were evaluated. RESULTS: The plasma concentration-time curves of Matrifen (Test) and Durogesic DTrans (Reference) were similar. The geometric least square means of the Test/Reference ratio (90% confidence intervals [CI]) were within the range of 80-125%, demonstrating bioequivalence of Matrifen and Durogesic DTrans: AUC(0-tlast) 92.5 (CI 88.7-96.4), AUC(0-inf) 91.7 (CI 88.0-95.7), and C(max) 98.3 (CI 92.9-104.1). After 72 h application, Matrifen had a more efficient utilization of fentanyl (mean+/-SD 82.3+/-9.43%) than Durogesic DTrans (52.3+/-12.8%), with substantially lower residual fentanyl in patch after use. The pharmacokinetic parameters showed lower intra- and inter-subject variability for Matrifen than for Durogesic DTrans patch. CONCLUSIONS: Despite different technologies, the transdermal fentanyl patches Matrifen and Durogesic DTrans are bioequivalent. Compared with Durogesic DTrans, the Matrifen patch had lower initial and lower residual fentanyl content, as well as lower intra- and inter-subject variability, allowing reproducible drug delivery and reliable analgesia.

Intrathecal therapy: what has changed with the introduction of ziconotide.

Administering drugs into the intrathecal space is becoming more popular in the treatment of patients with intractable pain or intolerable side effects of systemic analgesic treatments. Although morphine and ziconotide are the only intrathecal analgesics currently approved by regulatory authorities in the U.S. (Food and Drug Administration) and Europe (national-level approval by individual countries for morphine and European Agency for the Evaluation of Medicinal Products approval for ziconotide), a wide variety of opioid and non-opioid drugs are being used in this way. There is no official guidance concerning the selection of these drugs or their use in combinations and a paucity of efficacy and safety data from randomized controlled trials. The polyanalgesic initiative aims to summarize the current knowledge and to facilitate rational choices of intrathecal drug and drug combinations for the management of chronic pain. The most recent polyanalgesic consensus recommendations were published in 2007. In this review, we shall examine these recommendations, which are tailored toward those practicing intrathecal analgesia in the U.S., and discuss how they should be implemented in Europe, where the healthcare systems and regulations of the medical authorities are different.

Clinical update on the pharmacology, efficacy and safety of transdermal buprenorphine.

Buprenorphine was not used widely in clinical practice over many years, mainly due to analgesic potency and clinical safety concerns based on misinterpreted animal data. Contrary to previous concerns, however, no analgesic ceiling effect and no antagonism of combined pure mu-opioid receptor agonists is seen within the therapeutic dose range. In recent studies, buprenorphine could be effectively and safely combined with full mu-agonists, and switching between buprenorphine and another opioid provided comparable pain relief based on equianalgesic doses. Moreover, buprenorphine exerts an antihyperalgesic effect, which is due -- at least in part -- to antagonistic activity at kappa-opioid receptors. Buprenorphine pharmacokinetics are not altered by advanced age or renal dysfunction. In addition, the risk of respiratory depression is lower than with other opioids including morphine, hydromorphone, methadone and fentanyl. Unlike morphine and fentanyl, there is no immunosuppressive activity with buprenorphine at therapeutic analgesic doses. Transdermal buprenorphine has significantly improved the clinical use of the drug, providing continuous buprenorphine release for up to 96 h. In clinical trials, patients receiving transdermal buprenorphine experienced significantly greater pain relief, better sleep, and a reduced need for rescue therapy, compared to placebo. Large-scale post-marketing studies have confirmed the effectiveness of transdermal buprenorphine in treating moderate-to-severe cancer and non-cancer pain including neuropathic syndromes. Finally, the comparably low incidence of CNS adverse events and constipation, and the possibility of use in severe renal dysfunction without a need for dose adjustment make buprenorphine well suited for chronic pain management in at-risk patients, such as diabetics, elderly or renally impaired individuals including those requiring haemodialysis.

A randomized, open, parallel group, multicenter trial to investigate analgesic efficacy and safety of a new transdermal fentanyl patch compared to standard opioid treatment in cancer pain.

A new 72-hour transdermal fentanyl matrix patch has been designed, which has a 35%-50% reduction of the absolute fentanyl content compared with other currently available transdermal fentanyl patches that are using the matrix technology. The new patch has previously been shown to be pharmacokinetically bioequivalent to the marketed fentanyl patch. To determine noninferiority in efficacy in cancer patients and to compare safety, a clinical trial comparing the new fentanyl patch with standard oral or transdermal opioid treatment was planned. The design was an open, parallel group, multicenter trial, in which 220 patients were randomized to receive either the fentanyl patch or standard opioid treatment for 30 days. The primary efficacy variable, pain intensity (PI) on a 0-10-point numerical rating scale, was recorded once daily. The primary endpoint was the relative area under the curve of PI expressed as a percentage of the maximum possible PI area under the curve. Any adverse events were recorded; four tolerability endpoints, constipation, nausea, daytime drowsiness, and sleeping disturbances, were assessed daily. Noninferiority was shown; the upper 95% confidence interval limits of the mean difference in relative PI area under the curve between the fentanyl patch and standard opioid treatment were less than 10% for both the intention-to-treat and per-protocol populations. Scores for the tolerability endpoints were similar in the treatment groups. The new fentanyl matrix patch with a lower drug load was found noninferior and as safe as established standard oral and transdermal opioid treatment.

Lack of analgesia by oral standardized cannabis extract on acute inflammatory pain and hyperalgesia in volunteers.

BACKGROUND: Cannabinoid-induced analgesia was shown in animal studies of acute inflammatory and neuropathic pain. In humans, controlled clinical trials with Delta-tetrahydrocannabinol or other cannabinoids demonstrated analgesic efficacy in chronic pain syndromes, whereas the data in acute pain were less conclusive. Therefore, the aim of this study was to investigate the effects of oral cannabis extract in two different human models of acute inflammatory pain and hyperalgesia. METHODS: The authors conducted a double-blind, crossover study in 18 healthy female volunteers. Capsules containing Delta-tetrahydrocannabinol-standardized cannabis extract or active placebo were orally administered. A circular sunburn spot was induced at one upper leg. Heat and electrical pain thresholds were determined at the erythema, the area of secondary hyperalgesia, and the contralateral leg. Intradermal capsaicin-evoked pain and areas of flare and secondary hyperalgesia were measured. Primary outcome parameters were heat pain thresholds in the sunburn erythema and the capsaicin-evoked area of secondary hyperalgesia. Secondary measures were electrical pain thresholds, sunburn-induced secondary hyperalgesia, and capsaicin-induced pain. RESULTS: Cannabis extract did not affect heat pain thresholds in the sunburn model. Electrical thresholds (250 Hz) were significantly lower compared with baseline and placebo. In the capsaicin model, the area of secondary hyperalgesia, flare, and spontaneous pain were not altered. CONCLUSION: To conclude, no analgesic or antihyperalgesic activity of cannabis extract was found in the experiments. Moreover, the results even point to the development of a hyperalgesic state under cannabinoids. Together with previous data, the current results suggest that cannabinoids are not effective analgesics for the treatment of acute nociceptive pain in humans.