Tapering off long-term opioid therapy in chronic non-cancer pain patients: A randomized clinical trial.

BACKGROUND: The indications for initiating long-term opioid treatment (L-TOT) for chronic non-cancer pain (CNCP) are often unclear and associated with problematic use. This study aimed at evaluating the efficacy of stabilizing opioid therapy followed by a sequential opioid tapering off program in CNCP patients. METHODS: A randomized clinical trial with a medications stabilization period (Phase 1) was followed by an opioid tapering off program (Phase 2). In Phase 2, patients were randomized to Control Group (stable treatment) or Taper off Group (sequential opioid dose reduction) and assessed at baseline, after stabilization and up to 6 months. Primary outcomes: measures of cognitive function; secondary outcomes: pain, sleep, rest, quality of life, depression, anxiety, opioid misuse and opioid withdrawal symptoms. RESULTS: In all, 274 patients were screened; 75 were included, out of which 40 dropped out before Phase 2. Those who succeeded Phase 1 (n = 35) had weak/moderate improvements of psychomotor function (p = 0.020), sleeping hours (p = 0.031), opioid withdrawal symptoms (p = 0.019), measures of quality of life (p ≤ 0.043) and opioid misuse scores (p = 0.003). In Phase 2, patients in Taper off Group (n = 15) experienced stable pain intensity and felt significantly more rested at third assessment than the Control Group (n = 20). CONCLUSIONS: The opioid tapering off program was not successful due to the vast number of dropouts. Phase 1 was associated with weak to moderate improvements on psychomotor function, sleeping, opioid withdrawal symptoms, quality of life and reduced risk of opioid misuse. In the intervention group of Phase 2, pain intensity was stable and patients felt more rested. SIGNIFICANCE: This trial showed that sequential tapering off L-TOT in CNCP patients may be an unfeasible approach. However, improvements after opioid treatment stabilization were achieved and stable pain intensity in those tapered off may encourage the development of more refined programs.

Long-term opioid therapy in Denmark: A disappointing journey.

BACKGROUND: Longitudinal population-based studies of long-term opioid therapy (L-TOT) in chronic non-cancer pain (CNCP) patients are sparse. Our study investigated incidence and predictors for initiating L-TOT and changes in self-rated health, pain interference and physical activities in long-term opioid users. METHODS: Data were obtained from the national representative Danish Health and Morbidity Surveys and The Danish National Prescription Registry. Respondents with no dispensed opioids the year before the survey were followed from 2000 and from 2005 until the end of 2012 (n = 12,145). A nationally representative subsample of individuals (n = 2015) completed the self-administered questionnaire in both 2000 and 2013. Collected information included chronic pain (≥6 months), health behaviour, self-rated health, pain interference with work activities and physical activities. Long-term users were defined as those who were dispensed at least one opioid prescription in six separate months within a year. RESULTS: The incidence of L-TOT was substantially higher in CNCP patients at baseline than in others (9/1000 vs. 2/1000 person-years). Smoking behaviour and dispensed benzodiazepines were significantly associated with initiation of L-TOT in individuals with CNCP at baseline. During follow-up, L-TOT in CNCP patients increased the likelihood of negative changes in pain interference with work (OR 9.2; 95% CI 1.9-43.6) and in moderate activities (OR 3.7; 95% CI 1.1-12.6). The analysis of all individuals indicated a dose-response relationship between longer treatment duration and the risk of experiencing negative changes. CONCLUSIONS: Individuals on L-TOT seemed not to achieve the key goals of opioid therapy: pain relief, improved quality of life and functional capacity. SIGNIFICANCE: Long-term opioid therapy does not seem to provide pain relief, improvement in HRQOL and physical capacity in CNCP patients in a general population.

Chronic non-cancer pain and the epidemic prescription of opioids in the Danish population: trends from 2000 to 2013.

BACKGROUND: Chronic pain has serious consequences for individuals and society. In addition, opioid prescription for chronic non-cancer pain (CNCP) has become more frequent. This study aims to examine the trends regarding the prevalence of CNCP, dispensed opioids, and concurrent use of benzodiazepine (BZD)/BZD-related drugs in the Danish population. METHODS: Data from the cross-sectional national representative Danish Health and Morbidity Surveys (2000, 2005, 2010, and 2013) were combined with The Danish National Prescription Registry at an individual level. The study populations varied between 5000 and 13,000 individuals ≥16 years (response rates: 51-63%). Respondents completed a self-administered questionnaire, which included the analyzed items on identification of chronic pain (≥6 months). RESULTS: From 2000 to 2013, the prevalence of CNCP increased and subsequently the annual prevalence of opioid use from 4.1% to 5.7% among CNCP individuals. Higher CNCP prevalence was related to female gender, no cohabitation partner, short education, non-Western origin, and overweight/obesity. In addition, women with CNCP, especially >65 years, became more frequent users of opioids and used higher doses than men. Concurrent use of BZD/BZD-related drugs decreased (13%) from 2010 to 2013, still one-third of long-term opioid user were co-medicated with these drugs. CONCLUSIONS: The use of opioids has increased in Denmark, especially among elderly women. The concurrent use of BZD/BZD-related drugs has decreased from 2010 to 2013, but still one-third of long-term opioid users were co-medicated.

Renal function and symptoms/adverse effects in opioid-treated patients with cancer.

BACKGROUND: Renal impairment and the risk of toxicity caused by accumulation of opioids and/or active metabolites is an under-investigated issue. This study aimed at analysing if symptoms/adverse effects in opioid-treated patients with cancer were associated with renal function. METHODS: Cross-sectional multicentre study (European Pharmacogenetic Opioid Study, 2005-2008), in which 1147 adult patients treated exclusively with only one of the most frequently reported opioids (morphine/oxycodone/fentanyl) for at least 3 days were analysed. Fatigue, nausea/vomiting, pain, loss of appetite, constipation and cognitive dysfunction were assessed (EORTC QLQ-C30). Glomerular filtration rate (GFR) was estimated using Cockcroft-Gault (CG), Modification of Diet in Renal Disease (MDRD), and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI Creatinine) equations. RESULTS: Mild to severe low GFR was observed among 40-54% of patients. CG equation showed that patients with mild and moderate/severe low GFR on morphine treatment had higher odds of having severe constipation (P < 0.01) than patients with normal GFR. In addition, patients with moderate/severe low GFR on morphine treatment were more likely to have loss of appetite (P = 0.04). No other significant associations were found. CONCLUSION: Only severe constipation and loss of appetite were associated with low GFR in patients treated with morphine. Oxycodone and fentanyl, in relation to the symptoms studied, seem to be safe as used and titrated in routine cancer pain care.

The evidence of neuraxial administration of analgesics for cancer-related pain: a systematic review.

BACKGROUND: The present systematic review analysed the existing evidence of analgesic efficacy and side effects of opioids without and with adjuvant analgesics delivered by neuraxial route (epidural and subarachnoid) in adult patients with cancer. METHODS: Search strategy was elaborated with words related to cancer, pain, neuraxial route, analgesic and side effects. The search was performed in PubMed, EMBASE, and Cochrane for the period until February 2014. Studies were analysed according to methods, results, quality of evidence, and strength of recommendation. RESULTS: The number of abstracts retrieved was 2147, and 84 articles were selected for full reading. The final selection comprised nine articles regarding randomised controlled trials (RCTs) divided in four groups: neuraxial combinations of opioid and adjuvant analgesic compared with neuraxial administration of opioid alone (n = 4); single neuraxial drug in bolus compared with continuous administration (n = 2); single neuraxial drug compared with neuraxial placebo (n = 1); and neuraxial opioid combined with or without adjuvant analgesic compared with other comprehensive medical management than neuraxial analgesics (n = 2). The RCTs presented clinical and methodological diversity that precluded a meta-analysis. They also presented several limitations, which reduced study internal validity. However, they demonstrated better pain control for all interventions analysed. Side effects were described, but there were few significant differences in favour of the tested interventions. CONCLUSION: Heterogeneous characteristics and several methodological limitations of the studies resulted in evidence of low quality and a weak recommendation for neuraxial administration of opioids with or without adjuvant analgesics in adult patients with cancer.

Evidence of peripheral nerve blocks for cancer-related pain: a systematic review.

The European Association for Palliative Care has initiated a comprehensive program to achieve an over-all review of the evidence of multiple cancer pain management strategies in order to extend the current guideline for treatment of cancer pain. The present systematic review analyzed the existing evidence of analgesic efficacy for peripheral nerve blocks in adult patients with cancer. A search strategy was elaborated with words related to cancer, pain, peripheral nerve and block. The search was performed in PubMed, EMBASE, and Cochrane for the period until February 2014. The number of abstracts retrieved was 155. No controlled studies were identified. Sixteen papers presented a total of 79 cases. The blocks applied were paravertebral blocks (10 cases), blocks in the head region (2 cases), plexus blocks (13 cases), intercostal blocks (43 cases) and others (11 cases). In general, most cases reported good pain relief and no side effects. The use of peripheral blocks is based upon anecdotal evidence. However, this review only demonstrates the lack of studies, which does not equal a lack of effectiveness.

Pain characteristics and management of inpatients admitted to a comprehensive cancer centre: a cross-sectional study.

AIMS: This prospective, cross-sectional study aimed to assess cancer pain and its management in an inpatient setting at a comprehensive cancer centre in Denmark. METHODS: One hundred and eighty-eight inpatients with cancer were invited to participate (May/June 2011). Demographics, diagnoses, World Health Organization performance status, health-related quality of life, pain and data regarding analgesic treatment were registered. RESULTS: One hundred and thirty-four (71.3%) patients agreed to participate in the study. Most frequent diagnoses were leukaemia (27.6%) and lung cancer (14.2%). A high prevalence of pain was observed, 65.7%. Thirty-two per cent reported moderate to severe pain when it was at its worst, 96% reported no or mild pain when it was at its least. Nearly 22% reported moderate to severe pain when the pain was categorised as average. Breakthrough pain episodes were reported by 30.5%. Adjuvant medication was sparsely used and not always correctly indicated. Out of 88 patients with pain, 62.5% were left untreated according to the Electronic Medication System. Higher health-related quality of life was associated with lower pain intensity. The use of opioids with or without adjuvants was associated with higher pain intensity and higher number of breakthrough pain episodes. CONCLUSIONS: Approximately two thirds of inpatients reported pain and one third had breakthrough pain. A substantial number of patients with pain were left untreated. Opioid-treated patients reported highest pain intensity and number of breakthrough episodes; however, analgesic medication seemed to be underused. Measures to improve pain assessment and management are highly required.

Cognitive function in patients with chronic pain treated with opioids: characteristics and associated factors.

BACKGROUND: The paucity of studies regarding cognitive function in patients with chronic pain, and growing evidence regarding the cognitive effects of pain and opioids on cognitive function prompted us to assess cognition via neuropsychological measurement in patients with chronic non-cancer pain treated with opioids. METHODS: In this cross-sectional study, 49 patients were assessed by Continuous Reaction Time, Finger Tapping, Digit Span, Trail Making Test-B and Mini-mental State Examination tests. Linear regressions were applied. RESULTS: Patients scored poorly in the Trail Making Test-B (mean = 107.6 s, SD = 61.0, cut-off = 91 s); and adequately on all other tests. Several associations among independent variables and cognitive tests were observed. In the multiple regression analyses, the variables associated with statistically significant poor cognitive performance were female sex, higher age, lower annual income, lower schooling, anxiety, depression, tiredness, lower opioid dose, and more than 5 h of sleep the night before assessment (P < 0.05). CONCLUSIONS: Patients with chronic pain may have cognitive dysfunction related to some reversible factors, which can be optimized by therapeutic interventions.