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.

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.

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.

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.

Decrease in suicide among the individuals treated with antidepressants: a controlled study of antidepressants in suicide, Sweden 1995-2005.

OBJECTIVE: Ecological studies have demonstrated a substantial decrease in suicide in parallel with an increase in the use of antidepressants. Causality cannot, however, be inferred from such studies. The aim of this study was to test on the individual level the hypothesis that treatment with antidepressant medication has been a substantially contributing cause of the decrease in suicide. METHOD: Time trends in the detection of antidepressants and five 'control medications' in the forensic toxicological screening of 16 937 suicides and 33 426 controls in Sweden 1995-2005. RESULTS: The expected number of antidepressant-positive suicides in 2005 was 409 if the hypothesis was true and 603 if it was false. The observed number in 2005 was 420. The control medications were detected to the extent that was expected if not preventing suicide. CONCLUSION: The observed trend in the number of suicides with antidepressants was well predicted by the hypothesis that the increased use of antidepressants has been a substantially contributing cause of the decrease in suicide.

Propoxyphene and pain management in the elderly.

Pain is frequently reported and often undertreated in the elderly population. In light of these concerns, it is important to examine potentially ineffective or problematic pain medications. Propoxyphene is one such agent whose efficacy and safety have been questioned by researchers, clinicians and the U.S. Food and Drug Administration (FDA). Specifically, multiple studies have found propoxyphene to be no more effective than acetaminophen (APAP), yet propoxyphene causes opioid side effects and has been involved in many drug-related deaths. In addition, propoxyphene/APAP products are often prescribed at doses that exceed maximum values (49.2 percent of APAP/propoxyphene napsylate 100 prescriptions for South Dakota Medicaid patients exceeded the maximum daily dose). The relevance of propoxyphene use is seen by the 7.1 percent prevalence of propoxyphene prescriptions among the South Dakota Medicare beneficiaries, which is comparable to the 6.8 percent reported in the U.S. community-based Medicare population. Therefore, it is very important to consider alternatives to propoxyphene such as APAP, nonsteroidal anti-inflammatory drugs (rare use due to adverse effects) and other opioids, when managing elderly patients with pain.

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.

Acute postoperative pain predicts chronic pain and long-term analgesic requirements after breast surgery for cancer.

Postoperative pain and analgesic requirements may be associated with chronic pain. The aim of the study was to investigate this association. We studied 98 patients who had cancer breast surgery and served as controls in four previous studies, receiving placebo. We compared the pain and analgesic requirements 0-9 h and 1-6 days postoperatively: a) between patients with chronic pain 3 months postoperatively versus patients without and b) between those patients who consumed analgesics at home versus those who did not. Patients with chronic pain had experienced higher intensity pain at rest the first 9 postoperative hours (VAS-rest p = 0.033). Patients requiring analgesics at home had consumed postoperatively more opioids (p = 0.005) and more paracetamol (p = 0.037). These patients had experienced pain of higher intensity the first 9 postoperative hours (VAS-rest p = 0.022, VAS-movement p = 0.009) as well as during the six postoperative days (VAS-rest p = 0.013, VAS-movement p = 0.001). Higher intensities of acute postoperative pain are associated with chronic pain development. Higher analgesic needs and higher acute postoperatively pain intensity are associated with long-term analgesic consumption.

Dextropropoxyphene: welcome withdrawal from a French hospital's formulary.

Decision to exclude dextropropoxyphene from the list of drugs available at Toulouse University Hospital: more prescriptions of paracetamol as monotherapy and fewer prescriptions of step-2 analgesics.

[Drug therapy of opioid withdrawal]. / Tratamiento del Síndrome de Retiro de Opiáceos.

Although the opiate dependence is of low frequency in our midst, it is important to know its management because it requires medical treatment in most cases. At present, in our country, we may classify the different patient populations able to submit an opioid withdrawal syndrome in patients undergoing chronic treatment with opioids, patients in intensive care units, neonatal mother addicted patients and addicts from the general population or linked to the health system. Detoxification programs are typically characterized by a low rate of completion of treatment and a high rate of relapse. The opioid withdrawal syndrome is objectively and subjectively severe and moderate and the goals of the therapy for the Opiates Withdrawal Syndrome are: to prevent or reduce the objective and subjective symptoms of abstinence; to prevent or treat its most serious complications; to treat preexisting or concurrent psychiatric disorders; to reduce the frequency or severity of relapses and to rehabilitate in the long term.

Patterns of analgesic and anti-inflammatory medicine use by Australian veterans.

BACKGROUND: We examined analgesic and anti-inflammatory medicine use by Australian veterans before and after the introduction of selective Cox-2 inhibitors. METHODS: We studied cohorts of Gold Card-holding veterans using prescription data held by the Department of Veterans' Affairs for the period 1 July 1998 to 30 June 2004. Outcomes were volume dispensed, average daily quantity and cumulative incidence of use of paracetamol-containing and aspirin-containing medicines, non-selective and Cox-2-selective non-steroidal anti-inflammatory drugs (NSAIDs), tramadol and dextropropoxyphene. RESULTS: Overall, we found high levels of use of analgesic and anti-inflammatory medicines, which increased by 43% over the study period. Use of paracetamol-containing medicines was overtaken by NSAIDs in 1999/2000, corresponding to the introduction of the Cox-2-selective agents. Between 12 and 17% of Cox-2-selective medicine recipients were supplied amounts indicative of continuous use in relatively high doses and 51% of veterans received at least one relatively Cox-2-selective medicine (celecoxib, rofecoxib, meloxicam, diclofenac) by the end of the study period. Dextropropoxyphene use declined during the study and tramadol use increased 10-fold. CONCLUSION: This study shows very high levels of Cox-2 inhibitor use during the 6-year period. Cox-2-selective agents were more likely to be taken continuously and at higher doses than non-selective NSAIDs. This is relevant in view of the cardiovascular toxicity of this group of medicines. The study shows the value of using unit record dispensing data to assess drug use patterns. Linking dispensing records to hospital separation and mortality data will further enhance our ability to monitor drug safety.

Discussion forum.

Queries from European physicians about analgesic pharmacotherapy and responses from the author are presented. The topics addressed are the safety of propoxyphene, the risk of opioid dependence in nonmalignant pain, the role of ziconotide in pain management, and titration of sustained acting opioids.

Propoxyphene prescribing among populations older and younger than age 65 in a tertiary care hospital.

OBJECTIVE: To evaluate the proportion of patients aged 65 years and older who are prescribed propoxyphene (PP) versus those aged 65 and younger. DESIGN: Retrospective cross-sectional study. SETTING: Tertiary care facility. PARTICIPANTS: Adult patients admitted to the hospital between January 1, 2005, and June 30, 2005, and prescribed either hydrocodone (HC) or PP. MAIN OUTCOME MEASURE: The primary outcome measure was the proportion of PP orders prescribed for patients older versus younger than age 65. The secondary outcomes were to identify other variables occurring in higher proportions among patients who were prescribed PP versus HC. RESULTS: Of the 7,910 patients reviewed, 7,295 patients 92.2% were prescribed HC and 615 (7.8%) were prescribed PP. In a random sample of 1,065 patients, the prescribing pattern of PP for subjects > or =65 (221/615, 35.9%), was significantly higher than for HC (128/450, 28.4%), P = 0.0122. In a random selection of the larger sample, there were 44/108 (40.7%) in the PP group and 22/120 subjects (18.3%) > or =65 in the HC group (P = 0.0003). Among PP users, there was a higher percentage of females (P = 0.0150), more subjects with narcotic allergies (P < 0.0001), and more subjects with a history of fractures (P = 0.0232). CONCLUSIONS: Compared with nationally reported data, the rate of PP prescribing is relatively low. However, despite the recommendation to avoid the use of PP in elderly patients, its use occurs in a higher proportion of patients age 65 years or older than in younger patients. Studies evaluating the prescribing rates of potentially inappropriate medications should be put in context by comparing reported data with that of a younger cohort.

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.

Cyclosporin A does not reverse clinical resistance to paclitaxel in patients with relapsed non-Hodgkin's lymphoma.

PURPOSE: Cyclosporin A has been shown to reverse paclitaxel resistance in vitro by inhibiting P-gp function. Therefore, we determined whether addition of cyclosporine to paclitaxel reversed clinical paclitaxel resistance in patients with non-Hodgkin's lymphoma (NHL). PATIENTS AND METHODS: Patients with relapsed NHL were eligible if they had no intervening treatment after failure to respond to paclitaxel (200 mg/m2 over 3 hours), and if they had adequate marrow, renal, and hepatic function, no serious cardiac disease, no CNS involvement, and no antibodies to human immunodeficiency virus-1. A cyclosporin A bolus dose (5 mg/kg over 3 hours) was followed by intravenous infusion (15 mg/kg) over 24 hours. Six hours after the beginning of cyclosporin A, the immediately preceding paclitaxel dose was administered over 3 hours. All patients were premedicated with dexamethasone, diphenhydramine, and cimetidine. Response was assessed after two cycles, and those patients who achieved at least a partial response received a maximum of six courses. RESULTS: All 26 patients entered were assessable for toxicity and 25 were assessable for response. One patient whose disease had progressed during paclitaxel treatment had a partial remission after the addition of cyclosporin A (response rate, 4%; 95% confidence interval, 1% to 20%). Disease progressed in 17 patients (71%) and did not respond in seven (25%). Serum cyclosporin A A levels measured at the time of initiation of paclitaxel infusion were greater than 2,000 ng/mL during 81% of cycles. Treatment toxicity included peripheral neuropathy in 57%, myalgia or arthralgia in 30%, neutropenia in 53%, neutropenic fever in 8%, and thrombocytopenia in 42% of patients. One patient with preexisting asthma had an acute bronchospasm during the first cycle and was removed from the study. There were no renal or hepatic toxicity and no infectious or hemorrhagic deaths. CONCLUSION: Cyclosporin A administered on this schedule did not reverse established clinical resistance to paclitaxel, which suggests that P-gp-mediated drug efflux is unlikely to be the only cause of paclitaxel resistance in this patient population.

Propoxyphene form maintenance treatment of narcotic addiction.

Two studies compared propoxyphene napsylate (Darvon-N) with methadone hydrochloride as maintenance treatment for narcotic addicts. Most measures indicated that methadone was more effective than propoxyphene as a maintenance drug. Patients receiving propoxyphene reported more withdrawal-related symptoms early in treatment, tended to drop out sooner than patients receiving methadone, and were more likely to abuse heroin. Nevertheless, follow-up interviews at one and six months after treatment indicated no between-group differences in adjustment.

Therapeutic usefulness of propoxyphene napsylate in narcotic addiction.

The maximum doses of propoxyphene napsylate used to treat heroin addicts produce a degree of morphine-like activity equal to that produced by 20 to 25 mg/day of subcutaneously given morphine or 10 mg/day orally given methadone. This degree of activity wound be sufficient to ameliorate abstinence even in patients dependent on large doses of narcotics--an observation that supports the utility of propoxyphene napsylate in detoxification. On the other hand, only patients taking 10 mg/day or less of parenterally administered heroin could be maintained on maximum subtoxic levels of propoxyphene napsylate without abstinence signs or symptoms suggesting that propoxyphene napsylate would be less useful in maintenance therapy.