Correction: Predictors of opioid efficacy in patients with chronic pain: A prospective multicenter observational cohort study.

[This corrects the article DOI: 10.1371/journal.pone.0171723.].

Combination treatment of neuropathic pain: Danish expert recommendations based on a Delphi process.

BACKGROUND: Current Danish treatment algorithms for pharmacological treatment of neuropathic pain (NeP) are tricyclic antidepressants (TCA), gabapentin and pregabalin as first-line treatment for the most common NeP conditions. Many patients have insufficient pain relief on monotherapy, but combination therapy had not been included in guidelines until recently. Based on clinical empiricism and scientific evidence, a Delphi consensus process provided a consolidated guidance on pharmacological combination treatment of NeP. METHODS: A two-round virtual internet-based Delphi process with 6 Danish pain specialists was undertaken. In the first round, questions were answered individually and anonymously, whereas in the second round, the panel openly discussed first round's summary of outcomes. Combinations of pharmacological pain treatments, that is, pregabalin/gabapentin, TCAs, serotonin-norepinephrine reuptake inhibitors (SNRIs), selective serotonin reuptake inhibitors, opioids, other antiepileptics and cutaneous patches, were assessed based on both scientific and clinical practice experiences. The Centers for Disease Control and Prevention (CDC) grading system was used for evidence rating. RESULTS: Combination of pregabalin/gabapentin with TCA is useful in patients who do not gain sufficient pain relief or tolerate either drug in high doses, or to improve sleep disturbance. Also, combination of pregabalin/gabapentin and SNRIs is reasonably well documented and experienced by some experts to result in sufficient pain relief and fewer side effects than monotherapy. Good evidence on efficacy was found for the combination of pregabalin/gabapentin or TCAs and opioids, which was also frequently used in clinical practice. The evidence for combining TCAs and SNRIs is insufficient, although sometimes used in clinical practice despite the risk of serotonin syndrome. For localized NeP, combination therapy with cutaneous patches should be considered. There was insufficient scientific evidence for any pharmacologic combination therapies with selective serotonin reuptake inhibitors - as well as for other potential combinations. CONCLUSIONS: The study revealed that combination therapy is widely used in clinical practice and supported by some scientific evidence. However, further studies are needed.

Predictors of opioid efficacy in patients with chronic pain: A prospective multicenter observational cohort study.

Opioids are increasingly used for treatment of chronic pain. However, they are only effective in a subset of patients and have multiple side effects. Thus, studies using biomarkers for response are highly warranted. The current study prospectively examined 63 opioid-naïve patients initiating opioid use for diverse types of chronic pain at five European centers. Quantitative sensory testing, electroencephalography (EEG) recordings, and assessment of pain catastrophizing were performed prior to treatment. The co-primary outcomes were change from baseline in ratings of chronic pain and quality of life after 14 days of opioid treatment. Secondary outcomes included patient's global impression of clinical change and side effects. Logistic regression models adjusted for age and sex were used to identify biomarkers predictive for successful treatment, defined as at least a 30% reduction in average pain intensity or an improvement in quality of life of at least 10 scale points. Fifty-nine patients (94%) completed the study. The mean age was 55 ± 16 years and 69% were females. Pain reduction was predicted by cold pain intensity (OR: 0.69; P = 0.01), pain catastrophizing (OR: 0.82; P = 0.03), relative delta (OR: 0.76; P = 0.03) and beta EEG activity (OR: 1.18; P = 0.04) induced by experimental cold pain. None of the study variables were related to improvement in quality of life. For the first time, individual pain processing characteristics have been linked to opioid response in a mixed chronic pain population. This has the potential to personalize treatment of chronic pain and restrict opioid use to patients with high likelihood for response.

Hyperalgesia and myoclonus in terminal cancer patients treated with continuous intravenous morphine.

Eight cancer patients in the terminal stages of the disease treated with high doses of intravenous morphine developed hyperalgesia. All cases were retrospectively sampled from three different hospitals in Copenhagen. Five patients developed universal hyperalgesia and hyperesthesia which in 2 cases were accompanied by myoclonus. In 3 patients a pre-existing neuralgia increased to excruciating intensity and in 2 of these cases myoclonus occurred simultaneously. Although only few clinical descriptions of the relationship between hyperalgesia/myoclonus and high doses of morphine are available, experimental support from animal studies indicates that morphine, or its metabolites, plays a causative role for the observed behavioural syndrome. The possible mechanisms are discussed and treatment proposals given suggesting the use of more efficacious opioids with less excitatory potency in these situations.

Switching from high doses of pure µ-opioid agonists to transdermal buprenorphine in patients with cancer: a feasibility study.

BACKGROUND: Several myths on buprenorphine's pharmacology exist: possible analgesic ceiling effect, feasibility of combination with other opioid agonists, and the reversibility of side effects. Aim to evaluate: 1) if cancer patients receiving high doses of pure agonists could obtain adequate pain relief after switching to transdermal (TD) buprenorphine and 2) whether the numbers of breakthrough pain episodes after switching increased and whether they could be treated with the same doses of pure agonist as before switching. DESIGN: The prospective open multicenter study included outpatients with moderate-to-severe cancer pain satisfactorily controlled. SETTING: Patients were switched from the usual pure agonist to TD buprenorphine and were titrated to a stable dose. The assessments were: 1) daily self-assessment of pain intensity, numbers of rescue medications, and pain interference with sleep; 2) brief pain inventory; 3) pain relief and pain intensity; 4) quality of life; and 5) adverse events and symptoms. RESULTS: Eighteen patients receiving 150-516 mg of morphine/day were included. The buprenorphine dose at the end of the study varied between 52.5 and 140 µg/h. No difference in pain before and after switching was shown. The level of rescue doses was maintained. The patches were well tolerated. A significant decrease in fatigue and an increase in global health status were seen after the switch. CONCLUSION: It is feasible to switch cancer patients from high doses of pure µ-opioid agonists to TD buprenorphine without eliciting any antagonist effects, but the dose conversion factor is individual and the switching process should be tailored for the individual patient.

[Differences in the prescription of analgesics in the treatment of cancer pain in six Danish pain treatment units]. / Forskelle på ordinationsmønstret af analgetika ved behandling af cancersmerter på seks danske smertebehandlingsenheder.

30-40% of cancer patients suffer from pain at diagnosis while 70-80% of patients at progressed stages of the disease suffer from pain. Background pain is treated with long-acting opioids. Breakthrough pain can be treated with shorter acting non-opioid analgesics or opioids. The aim of this study was to describe the medical treatment of pain in cancer patients in connection with six Danish hospital units with special expertise in pain treatment. Differences in the prescription of analgesics were studied. The study was performed as a cross section study of prescribed analgesics. Data was collected by reviewing medical records. The study included 347 patients. A total of 278 patients out of 347 were treated with opioids for background pains. A significant difference was found (P < 0.001) in the frequency of prescribing morphine, oxycodone and fentanyl. For the treatment of background pain secondary analgesics were prescribed for 40% of the patients while 50% of the patients were treated with paracetamol and/or NSAID. According to the medical records 79% of the patients were prescribed analgesics for breakthrough pain. 73% of the 347 patients had strong opioids prescribed for breakthrough pain. For the treatment of background pain opioids were prescribed for the majority of the cancer patients. Morphine and oxycodone were prescribed most frequently. Secondary analgesics and paracetamol and/or NSAID were also prescribed for background pain. The strong opioids were prescribed for the treatment of breakthrough pain. Differences in the prescription of analgesics between the six hospital units were observed in this study.