Comparative risk-benefit profiles of weak opioids in the treatment of osteoarthritis: a network meta-analysis of randomized controlled trials.

BACKGROUND: Despite their poor tolerance, weak opioids are still the most commonly-prescribed medicine for osteoarthritis (OA)-related pain. The objective of this network meta-analysis was to comparatively examine the efficacy and safety of weak opioids in OA treatment. METHODS: Databases including PubMed, Embase, Cochrane Library and Web of Science were searched from inception to 4 April 2022 to retrieve randomized controlled trials (RCTs) comparing weak opioids with placebo or between one another in OA patients. Bayesian network meta-analysis was performed on the following outcomes of interest, namely the change-from-baseline score in pain relief, gastrointestinal (GI) adverse events (AEs), central nervous system (CNS) AEs, and total number of AEs (i.e. the number of subjects experiencing any AE for at least once) during follow-up. The surface under the cumulative ranking curve (SUCRA) was used to rank the effectiveness of each treatment and identify the best treatment. RESULTS: A total of 14 RCTs invoving four types of weak opioids were included in this meta-analysis. Compared to placebo, tramadol (standardized mean difference [SMD] = -0.34, 95% credible interval [CrI]: -0.53 to -0.18) and codeine (SMD = -0.39, 95% CrI: -0.79 to -0.04) were effective for pain relief, but involved a higher risk of GI AEs, CNS AEs and total number of AEs. Dextropropoxyphene demonstrated a significantly lower risk of GI AEs (OR = 0.28, 95%CrI: 0.17 to 0.51), CNS AEs (OR = 0.29, 95%CrI: 0.11 to 0.78) and total number of AEs (OR = 0.35, 95%CrI: 0.15 to 0.82) compared to codeine. Dihydrocodeine had a better safety profile in CNS AEs (SUCRA = 64.8%) and total number of AEs (SUCRA = 66.6%). CONCLUSIONS: The results of the present study confirmed that tramadol and codeine were effective drugs for the treatment of OA, but involved considerable safety issues. Dextropropoxyphene and dihydrocodeine exhibited a relatively good safety profile but their efficacy still warrant further investigation.

Prescription opioid analgesic use in France: Trends and impact on morbidity-mortality.

BACKGROUND: While data from USA and Canada demonstrate an opioid overdose epidemic, very little nation-wide European studies have been published on this topical subject. METHODS: Using a nationally representative sample of the French Claims database (>700,000 patients), the exhaustive nationwide hospital discharge database, and national mortality registry, all patients dispensed at least one prescription opioid (PO) in 2004-2017 were identified, to describe trends in PO analgesic use, shopping behaviour, opioid-related hospitalizations and deaths. Annual prevalence of PO use and shopping behaviour (≥1 day of overlapping prescriptions from ≥2 prescribers, dispensed by ≥3 pharmacies) was estimated. RESULTS: In 2004-2017, the annual prevalence of weak opioid use codeine, tramadol and opium rose by 150%, 123%, and 244%, respectively (p < 0.05). Strong opioid use increased from 0.54% to 1.1% (+104%, p < 0.05), significantly for oxycodone (+1950%). Strong opioid use in chronic noncancer pain rose by 88% (p < 0.05) and 1180% for oxycodone. Opioid shopping increased from 0.50% to 0.67% (+34%, p < 0.05), associated with higher mortality risk HR = 2.8 [95% confidence interval (CI): 1.2-6.4]. Opioid-related hospitalizations increased from 15 to 40 per 1,000,000 population (+167%, 2000-2017), and opioid-related deaths from 1.3 to 3.2 per 1,000,000 population (+146%, 2000-2015). CONCLUSIONS: This study provided a first European approach to a nationwide estimation with complete access to several national registries. In 2004-2017 in France, PO use excluding dextropropoxyphene more than doubled. The increase in oxycodone and fentanyl use, and nontrivial increasing trend in opioid-related morbidity-mortality should prompt authorities to closely monitor PO consumption in order to prevent alarming increases in opioid-related morbidity-mortality. SIGNIFICANCE: In 2004-2017, prescription opioid use in France at least doubled and oxycodone use increased particularly, associated with a nontrivial increase in opioid-related morbidity-mortality. Although giving no indication for an 'opioid epidemic,' these findings call for proper monitoring of opioid use.

Changing Trends in Opioid Use Among Patients With Rheumatoid Arthritis in the United States.

OBJECTIVE: Opioid prescribing recently has come under intense scrutiny. However, longitudinal patterns of prescription opioid receipt in a population-based cohort of patients with chronic pain, such as those with rheumatoid arthritis (RA), have not been well characterized. The aim of this study was to examine both trends over time and variability in individual physician prescribing of short-term and long-term use of opioids. METHODS: We identified a cohort of RA patients based on 2006-2014 Medicare data and evaluated longitudinal time trends in "regular" use of opioids. A separate analysis conducted in 2014 assessed rheumatologist-specific variability in regular use of opioid prescriptions in patients with RA. RESULTS: We identified 97,859 RA patients meeting the eligibility criteria. The mean age of the patients was 67 years, 80% were female, 82% were white, and 12% were African American. The most commonly used opioids were those that combined acetaminophen with hydrocodone or propoxyphene. Regular opioid prescribing increased slowly but peaked in 2010 before propoxyphene was withdrawn from the market. Following the withdrawal of propoxyphene, receipt of hydrocodone and tramadol increased commensurately, and overall opioid use declined only slightly. Factors associated with regular use of opioids included younger age, female sex, African American race, back pain, fibromyalgia, anxiety, and depression. Variability between US rheumatologists (n = 4,024) in prescribing the regular use of opioids for their RA patients was high; in the average rheumatologist's practice, 40% of RA patients used prescription opioids regularly. In almost half of the patients, at least some opioid prescriptions were written by a rheumatologist, and 14% received opioids that were co-prescribed concurrently by more than 1 physician. CONCLUSION: In the US, opioid use in older patients with RA peaked in 2010 and is now declining slightly. Withdrawal of propoxyphene from the US market in 2010 had minimal effect on overall opioid use, because use of propoxyphene was replaced by increased use of other opioids.

Opioid Analgesics and the Risk of Serious Infections Among Patients With Rheumatoid Arthritis: A Self-Controlled Case Series Study.

OBJECTIVE: Animal studies and in vitro human studies suggest that certain opioid analgesics impair crucial immune functions. This study was undertaken to determine whether opioid use is associated with increased risk of serious infection in patients with rheumatoid arthritis (RA). METHODS: We conducted a self-controlled case series analysis on a retrospective cohort of 13,796 patients with RA enrolled in Tennessee Medicaid in 1995-2009. Within-person comparisons of the risk of hospitalization for serious infection during periods of opioid use versus non-use were performed using conditional Poisson regression. Fixed confounders were accounted for by design; time-varying confounders included age and use of disease-modifying antirheumatic drugs, glucocorticoids, and proton-pump inhibitors. In additional analyses, risks associated with new opioid use, use of opioids known to have immunosuppressive properties, use of long-acting opioids, and different opioid dosages were assessed. Sensitivity analyses were performed to account for potential protopathic bias and confounding by indication. RESULTS: Among 1,790 patients with RA who had at least 1 hospitalization for serious infection, the adjusted incidence rate of serious infection was higher during periods of current opioid use compared to non-use, with an incidence rate ratio (IRR) of 1.39 (95% confidence interval [95% CI] 1.19-1.62). The incidence rate was also higher during periods of long-acting opioid use, immunosuppressive opioid use, and new opioid use compared to non-use (IRR 2.01 [95% CI 1.52-2.66], IRR 1.72 [95% CI 1.33-2.23], and IRR 2.38 [95% CI 1.65-3.42], respectively). Results of sensitivity analyses were consistent with the main findings. CONCLUSION: In within-person comparisons of patients with RA, opioid use was associated with an increased risk of hospitalization for serious infection.

A Randomized, Double-blind, Placebo-Controlled Crossover Trial of Oxymorphone Hydrochloride and Propoxyphene/Acetaminophen Combination for the Treatment of Neurogenic Claudication Associated With Lumbar Spinal Stenosis.

STUDY DESIGN: Randomized, double-blind, placebo-controlled, single-dose crossover study. OBJECTIVE: To test the analgesic efficacy of oxymorphone hydrochloride (OH) and propoxyphene/acetaminophen (PA) for patients with neurogenic claudication associated with lumbar spinal stenosis. SUMMARY OF BACKGROUND DATA: Although opioids are often prescribed for neurogenic claudication, no randomized controlled studies support their efficacy for this condition. Patients with neurogenic claudication are generally excluded from clinical trials or included with patients who have nonspecific chronic low back pain, yielding a heterogeneous study population with very different pathophysiologies and clinical presentations. METHODS: Participants received a single dose of each of the 3 treatments in random order. Treatments were separated by at least 3-day washout periods. The primary outcome variable was the time to first treadmill walking-induced moderate pain (≥4 out of 10 on a Numeric Rating Scale) (Tfirst) assessed 90 minutes after treatment administration. Secondary outcome measures included patient global assessment of low back pain, Roland-Morris Disability Questionnaire, Modified Brief Pain Inventory-Short Form, Oswestry Disability Index, and Swiss Spinal Stenosis Questionnaire. RESULTS: The study was prematurely terminated because of the removal of PA from the US market. Twenty-four patients were randomized; 21 completed all 3 treatment periods. There were no significant differences among the treatment groups with respect to the median Tfirst (OH-placebo: median [98.3% confidence limits]=-0.25 min [-6.54, 5.00]; PA-placebo: 0.02 min [-7.65, 4.90]; OH-PA: -0.27 min [-5.56, 6.66]). CONCLUSION: This trial failed to demonstrate a benefit of OH or PA in patients experiencing neurogenic claudication. Considering the potential negative side effects of chronic opioid use, additional research is necessary to evaluate the efficacy of sustained opioid treatment specifically for neurogenic claudication. LEVEL OF EVIDENCE: 2.

Consequences of dextropropoxyphene market withdrawal in elderly patients with chronic pain.

OBJECTIVE: Describe the consequences of dextropropoxyphene (DXP) market withdrawal on analgesic prescriptions and on the quality of therapeutic management of chronic pain. PATIENTS AND METHODS: From a cohort of non-institutionalised elderly patients with chronic pain recruited by general practitioners, we selected patients who were treated with DXP daily for at least 6 months just prior to DXP market withdrawal and who had an evaluation of pain and its impact on daily activities before and after DXP withdrawal. RESULTS: One hundred three patients took DXP daily for chronic pain. Immediately after DXP market withdrawal, 42 (40.8%), 55 (53.4%) and 3 (2.9%) patients were treated with step 1, 2 and 3 analgesics, respectively, and 3 patients (2.9%) were no longer receiving any analgesic medication. Among the 55 patients who continued on step 2 analgesics, 37 were treated with tramadol, 14 with codeine and 9 with opium. Pain intensity and the impact of pain on daily activities remained stable. CONCLUSION: DXP market withdrawal had no consequences on the intensity or impact of chronic pain in elderly patients.

The therapeutic management of chronic pain in ambulatory care patients aged 65 and over in France: the S.AGES Cohort. Baseline data.

OBJECTIVE: The main objective of the S.AGES (Elderly Subjects) cohort study is to describe the current therapeutic strategy for chronic pain in non-institutionalised elderly patients in France. METHODS: In this prospective cohort study, non-institutionalised patients aged 65 years and over with chronic pain were recruited by general practitioners (GP) across France. All medicinal and non- medicinal prescriptions were recorded at inclusion and will be followed up over 3 years via an eCRF. Data recorded at baseline are presented in this paper. RESULTS: Two hundred and sixty GPs enrolled 1379 evaluable patients between June 3rd, 2009 and June 3rd, 2011. Pain was mainly of a mechanical nature, due to osteoarthritis or common back pain. 80% of the patients had moderate or severe pain. More than a third of patients were treated with a step 1 analgesic (mainly paracetamol), and approximately 30% received a step 2 analgesic (23% dextropropoxyphene and 40.3% tramadol/paracetamol combination). Only 3% received step 3 analgesics; this rate remained low even in patients with severe pain. The proportion of patients treated with an antiepileptic was higher in case of neuropathic pain. More than 25% of patients did not receive any analgesic medication. CONCLUSION: The baseline S.AGES study results exhibit a well-balanced therapeutic management of chronic pain by GPs for ambulatory elderly patients. Clinicaltrials.org NCT01065909.

The effectiveness of national guidance in changing analgesic prescribing in primary care from 2002 to 2009: an observational database study.

BACKGROUND: Numerous national guidelines have been issued to assist general practitioners' safe analgesic prescribing. Their effectiveness is unclear. The objective of this study was to examine trends in general practitioners' prescribing behaviour in relation to national guidelines. METHODS: This was a retrospective observational database study of registered adult patients prescribed an analgesic (2002-2009) from the Consultations in Primary Care Archive--12 North Staffordshire general practices. Prescribing guidance from the UK Medicines Regulatory Health Authority (MHRA) regarding non-steroidal anti-inflammatory drugs (NSAIDs) and co-proxamol, and the National Institute for Health and Clinical Excellence (NICE) osteoarthritis (OA) management guidelines were considered. Analgesic prescribing rates were examined, arranged according to a classification of six equipotent medication groups: (1) basic analgesics; (2)-(5) increasingly potent opioids and (6) NSAIDs. In each quarter from 2002 to 2009, the number of patients per 10,000 registered population receiving a prescription for the first time from each group was determined. Quarters associated with significant changes in the underlying prescribing trend were determined using joinpoint regression. RESULTS: A significant decrease in incident co-proxamol and Cox-2 prescribing occurred around the time of the first MHRA advice to stop using them and were rarely prescribed thereafter. The new prescribing of weak analgesics (e.g., co-codamol 8/500) increased at this same time. Initiating topical NSAIDs significantly increased around the time of the NICE OA guidelines. CONCLUSIONS: Significant prescribing changes occurred when national advice and guidelines were issued. The effectiveness of this advice may vary depending upon the content and method of dissemination. Further evaluation of the optimal methods for delivering prescribing guidance is required.

Analgesic efficacy of tramadol/acetaminophen and propoxyphene/acetaminophen for relief of postoperative wound pain.

BACKGROUND/PURPOSE: Weak opioid combined with acetaminophen (APAP) has been proven to provide better analgesic efficacy and cause fewer complications than either drug alone. However, there are questions about whether different opioids, tramadol and propoxyphene, provide similar efficacy or safety. Thus, we investigated Ultracet (37.5 mg tramadol/325 mg APAP) and Depain-X (65 mg propoxyphene/650 mg APAP). The primary aims of this study were to compare the analgesic efficacy and adverse effects of single-dose oral Ultracet versus Depain-X in acute postoperative pain. MATERIALS AND METHODS: This was a randomized, open-label, active-controlled parallel study on patients with postsurgical pain. Sixty patients who sustained moderate postsurgical pain (visual analog scale(3)3 cm) after undergoing implantation of venous access were randomized to two groups to receive either Ultracetor Depain-X for postoperative analgesia. Assessment items included pain intensity and pain relief ratings at the first 4 hours, and adverse events. RESULTS: There were initially 107 patients who were enrolled in this trial, but up to 45 (42.1%) of them were withdrawn during the study. In these 62 patients who complied with treatment (Ultracet: Depain-X = 29: 33), pain relief scale indicated that Ultracet could provide a better analgesic effect than Depain-X provided at 1 hour (p < 0.05). At 4 hours, the pain score in the Ultracet group was significantly lower than that in the Depain-X group (p < 0.05). Adverse events, such as drowsiness, dizziness, and skin itching did not differ in both groups. CONCLUSION: Among patients with mild to moderate postoperative wound pain, single-dose Ultracet can provide slightly better analgesic efficacy than Depain-X in terms of onset and duration. Depain-X is no longer marketed in Europe, America, Taiwan and other countries, therefore, Ultracet can serve as a good substitute for treating postoperative pain.

Urinalysis-based comparative evaluation of pattern of use of dextropropoxyphene and buprenorphine among opioid-dependent subjects.

OBJECTIVE: In view of increasing safety concerns, there is a need to assess benefits of use of dextropropoxyphene as opioid substitution treatment, if any. This study aims at urinalysis-based comparative evaluation of pattern of use of dextropropoxyphene and buprenorphine among opioid-dependent subjects. SETTING: Laboratory of a tertiary care drug-dependence treatment center. PARTICIPANTS: Patients on buprenorphine and dextropropoxyphene therapy and their urinalysis records. INTERVENTIONS: Nonexperimental chart review method. MAIN OUTCOME MEASURE(S): "Use," "abuse, "and 'prescribed but not used rates" for buprenorphine and dextropropoxyphene were compared, using chi2-test with level of significance at p < 0.05. RESULTS: Rate of "use" and "abuse" was significantly high for dextropropoxyphene. Rate of 'prescribed but not used" was significantly high for buprenorphine (p < 0.05). CONCLUSIONS: Despite apparent benefits of dextropropoxyphene use in terms of better rates of "use" and 'prescribed but not used" as compared to buprenorphine, one needs to review the situation in light of recent reports of adverse effects with dextropropoxyphene and limited resources available.

A double-blind randomized crossover study to evaluate the timing of pregabalin for third molar surgery under local anesthesia.

PURPOSE: This double-blind randomized crossover study compared the analgesic efficacy of pre- and postoperative administration of oral pregabalin 75 mg using a postsurgical dental pain model. MATERIALS AND METHODS: Patients requiring third molar surgery in 2 separate stages under local anesthesia were recruited. They were given pregabalin 75 mg either 1 hour before or after their first surgical extraction. They then received the same dose of pregabalin at their second surgical extraction, but those who received it before surgery received it postsurgery, and vice versa. Postoperative analgesic effects were assessed at postoperative hours 2, 4, 8, 12, 24, 48, and 72. Time to first analgesic, analgesic consumption and adverse events were also evaluated. RESULTS: Forty patients were recruited, and 34 completed the study. The area under curves for numerical rating scale pain scores 1 to 24 hours were significantly lower at rest but not during mouth opening for patients receiving postoperative pregabalin (P < .048). Pain relief was similar for the period of 24 to 72 hours. No significant difference was found in time to first analgesic, total analgesic consumption, and side effects between preoperative and postoperative groups. No difference in the incidence of adverse events was noticed in relation to the timing of pregabalin administration. CONCLUSIONS: Postoperative administration of oral pregabalin 75 mg appears to offer better analgesic efficacy than preoperative administration after third molar surgery under local anesthesia.

Physician perspective on propoxyphene as a potentially inappropriate medication in Tennessee.

Medicare Part D data from the Quality Improvement Organization's 9th Statement of Work drug safety indicator project under the direction of the Centers for Medicare & Medicaid Services define the potentially inappropriate medications (PIMs) list for Tennessee. These data reveal propoxyphene as the main contributor to the state's PIM rate. In Tennessee, PIM and drug-drug interaction (DDI) rates indicate propoxyphene as the most prescribed medication among elderly patients despite decades of attention for potentially adverse effects. During this project, physicians agreed that PIM rates are too high, but disagreed in approach preference, i.e., administrative limits and bans versus a proactive educational approach. Physicians were interested in participating in quality improvement by using individual pharmacy data to influence prescribing patterns. Exploring alternatives in research and survey, a potential and reachable point of intervention was found, a prescribing paradigm proposed by researchers to improve outcomes by reducing adverse effects in minimizing PIMs and DDIs.

A prospective evaluation of 2 different pain management protocols for total hip arthroplasty.

Pain management after total hip arthroplasty has improved dramatically in the past decade. However, most protocols use opioid medications for pain control. In the current study, 100 patients were prospectively selected to receive a traditional narcotic-based patient-controlled analgesia protocol or a nonnarcotic oral protocol for pain management after primary total hip arthroplasty. Therapy programs were similar for both groups. Postoperatively, patients were followed daily for opioid use, medication adverse effects, pain control, and overall satisfaction. The nonnarcotic oral group showed lower mean pain scores during the first 24 hours after surgery. The satisfaction rate was high in both groups. Both protocols provided adequate pain control after total hip arthroplasty; the nonnarcotic pain management protocol resulted in significantly decreased opioid consumption and fewer adverse effects.

[Assessment of quality in day-case hand surgery]. / Démarche d'assurance qualité en chirurgie ambulatoire de la main.

OBJECTIVE: To determine the level of satisfaction in terms of pain relief and comfort among patients receiving different postoperative analgesia protocols after hand surgery under regional anaesthesia in a day care unit. METHODS: Cohort study among patients after hand surgery under regional anaesthesia during two consecutive three months time periods, with patient stratification according to the expected pain level with different balanced analgesia protocols (group A: carpal tunnel, group B: other surgery without bone involvement, group C: bone surgery). A telephone survey, scoring analgesia and comfort, each with a numerical (0-10) scale was conducted on days 1 and 7. During the first period analgesia for groups A and B was the same (acetaminophen-dextropropoxyphene or acetaminophen-codeine) and group C patients were treated with acetaminophen-ketoprofen-tramadol. In the second period analgesia was reduced for group A (acetaminophen alone) and increased for group B (acetaminophen-ketoprofen-tramadol) and group C (duration increased from 3 to 7 days). RESULTS: For carpal tunnel surgery, analgesia with acetaminophen alone was efficient, (Pain scale [PS] d0=2[0-10], PS d1=1 [0-10] and PS d2-d4=0,5 [0-10]). This surgery does not elicit important pain, there is no benefit in adding other analgesics. For group B, a significant improvement in postoperative pain was observed (postoperative d1 p<0.03) with a major increase in side effects (2/57 vs 17/48 p<0.001). For group C, therapeutic changes were ineffective (PS d0=2 vs 3.5 et PS d1=3 vs 5 [NS]) and we noticed an increase in side effects (p<0.05). One third of all patients are totally satisfied on day 7, logistic regression showing the role of inefficient analgesia in late postoperative period (PS>2 between d2-d4). Between day 1 and day 7, 20% of the patients change their point of view, those who feel less satisfied on day 7 complained of a more severe postoperative pain between day 2 and 4 (p<0.001) and between day 5-7 (p<0.01). CONCLUSION: For hand surgery on day case, quality of late postoperative analgesia (day 2-day 7) is strongly related to patient's satisfaction on day 7.

Use of dextropropoxyphene + acetaminophen fixed-dose combination in psychiatric hospital in Bahrain: is there a cause for concern?

There are concerns about the safety of the dextropropoxyphene and acetaminophen fixed-dose combination, particularly in patients with psychiatric morbidity, which has led to a phased withdrawal of this fixed-dose combination in many countries. A retrospective prescription audit was conducted to evaluate the dextropropoxyphene + acetaminophen fixed-dose combination prescribing pattern in the major psychiatric hospital of Bahrain. The data analysis was performed using SPSS/PC+ version 14.0. Prescriptions with the dextropropoxyphene + acetaminophen fixed-dose combination comprised 11.8% of all dispensed prescriptions and in most instances for outpatients undergoing substance abuse rehabilitation. Nearly half of the patients received >or=20 tablets of this fixed-dose combination (mean +/- SD: 30.9 +/- 13.1; range 20-126) as multiple doses. The dextropropoxyphene + acetaminophen fixed-dose combination was often co-prescribed with psychotropics, such as benzodiazepines (BZDs) (25.4%), BZDs + antidepressants (62.9%), BZDs + antipsychotics (3.7%) and BZDs + anticonvulsants (1.9%). Approximately 40% of prescriptions with the dextropropoxyphene + acetaminophen fixed-dose combination were written 'as required' (prn), basis. Despite poor safety and efforts to restrict or withdraw worldwide, the dextropropoxyphene + acetaminophen fixed-dose combination continues to be irrationally prescribed to outpatients undergoing substance abuse rehabilitation in Bahrain. Health policy decision-makers should introduce a phased withdrawal of this drug from clinical use. In the meanwhile, it is important to create awareness among prescribers of the risks associated with over-dosage of the dextropropoxyphene + acetaminophen fixed-dose combination and its interaction with other psychotropic medications.