A Single Site Population Study to Investigate CYP2D6 Phenotype of Patients with Persistent Non-Malignant Pain.

Background and Objectives: Codeine requires biotransformation by the CYP2D6 enzyme, encoded by the polymorphic CYP2D6 gene, to morphine for therapeutic efficacy. CYP2D6 phenotypes of poor, intermediate, and ultra-rapid metabolisers are at risk of codeine non-response and adverse drug reactions due to altered CYP2D6 function. The aim of this study was to determine whether genotype, inferred phenotype, and urinary and oral fluid codeine O-demethylation metabolites could predict codeine non-response following a short course of codeine. Materials and Methods: There were 131 Caucasians with persistent pain enrolled. Baseline assessments were recorded, prohibited medications ceased, and DNA sampling completed before commencing codeine 30 mg QDS for 5 days. Day 4 urine samples were collected 1-2 h post morning dose for codeine O-demethylation metabolites analysis. Final pain assessments were conducted on day 5. Results: None of the poor, intermediate, ultra-rapid metabolisers and only 24.5% of normal metabolisers responded to codeine. A simple scoring system to predict analgesic response from day 4 urinary metabolites was devised with overall prediction success of 79% (sensitivity 0.8, specificity 0.78) for morphine and 79% (sensitivity 0.76, specificity 0.83) for morphine:creatinine ratio. Conclusions: In conclusion, this study provides tentative evidence that day 4 urinary codeine O-demethylation metabolites could predict non-response following a short course of codeine and could be utilised in the clinical assessment of codeine response at the point of care to improve analgesic efficacy and safety in codeine therapy. We offer a scoring system to predict codeine response from urinary morphine and urinary morphine:creatinine ratio collected on the morning of day 4 of codeine 30 mg QDS, but this requires validation before it could be considered for use to assess codeine response in clinical practice.

Spinal cord stimulation for visceral pain--a novel approach.

BACKGROUND: Spinal cord stimulation and dorsal column stimulation have been used successfully in the management of visceral pain for many years. A novel technique of ventral column stimulation has been used in our institute with good outcomes since 2007. We describe a retrospective series of 26 patients with visceral neuropathic pain who were treated with neuromodulation. METHODS: Patients with either dermatomal hyperalgesia or sympathetically mediated neuropathic abdominal pain who had been treated with spinal cord stimulation were assessed. An independent observer conducted a face-to-face interview with each patient to collect data including demography, electrode placement, electrode mapping, and outcomes. RESULTS: There was significant reduction in visual analog pain scores from a median 9 at baseline to 4 at 26 months (p ≤ 0.05). Reduction in opioid consumption was very significant from a baseline median oral morphine equivalent of 160 mg to 26 mg (p < 0.001). In addition, quality of life, activities of daily living, and patient global impression of change improved. CONCLUSION: There is a need to further investigate the use of ventral stimulation for visceral pain syndromes. This would need multicenter trials to collect adequate numbers of patients to allow hypothesis testing to underpin recommendations for future evidence-based therapies.

Bolus intrathecal injection of ziconotide (Prialt®) to evaluate the option of continuous administration via an implanted intrathecal drug delivery (ITDD) system: a pilot study.

OBJECTIVES: This study evaluated efficacy and safety of bolus doses of ziconotide (Prialt®, Eisai Limited, Hertfordshire, UK) to assess the option of continuous administration of this drug via an implanted intrathecal drug delivery system. MATERIALS AND METHODS: Twenty adults with severe chronic pain who were under consideration for intrathecal (IT) therapy were enrolled in this open label, nonrandomized, pilot study. Informed consent was obtained. Demographics, medical/pain history, pain scores, and concomitant medications were recorded. A physical examination was performed. Creatine kinase was measured. Initial visual analog scale (VAS), blood pressure, heart rate, and respiratory rate were recorded. All patients received an initial bolus dose of 2.5 mcg ziconotide; the dose in the subsequent visits was modified according to response. Subsequent doses were 2.5 mcg, 1.2 mcg, or 3.75 mcg as per protocol. A good response (≥30% reduction in baseline pain VAS) with no side-effects on two occasions was considered a successful trial. Data were analyzed using a generalized estimating equations model, with pain VAS as the outcome and time (seven time points; preinjection and one to six hours postinjection) as the predictor. RESULTS: Generalized estimating equations analysis of summary measures showed a mean reduction of pain VAS of approximately 25% at the group level; of 11 responders, seven underwent pump implantation procedure, two withdrew because of adverse effects, one refused an implant, and one could not have an implant (lack of funding from the Primary Care Trust). CONCLUSIONS: Our data demonstrated that mean VAS was reduced by approximately 25% at the group level after IT ziconotide bolus. Treatment efficacy did not vary with sex, center, age, or pain etiology. Ziconotide bolus was generally well tolerated. Larger studies are needed to determine if bolus dosing with ziconotide is a good predictor of response to continuous IT ziconotide via an intrathecal drug delivery system.

Transcutaneous electric nerve stimulation (TENS) for cancer pain in adults.

BACKGROUND: Cancer-related pain is complex and multi-dimensional but the mainstay of cancer pain management has predominantly used a biomedical approach. There is a need for non-pharmacological and innovative approaches. Transcutaneous Electric Nerve Stimulation (TENS) may have a role in pain management but the effectiveness of TENS is currently unknown. This is an update of the original review published in Issue 3, 2008. OBJECTIVES: The aim of this systematic review was to determine the effectiveness of TENS for cancer-related pain in adults. SEARCH METHODS: The initial review searched The Cochrane Library, MEDLINE, EMBASE, CINAHL, PsychINFO, AMED and PEDRO databases in April 2008. We performed an updated search of CENTRAL, MEDLINE, EMBASE, CINAHL and PEDRO databases in November 2011. SELECTION CRITERIA: We included only randomised controlled trials (RCTS) investigating the use of TENS for the management of cancer-related pain in adults. DATA COLLECTION AND ANALYSIS: The search strategy identified a further two studies for possible inclusion. One of the review authors screened each abstract using a study eligibility tool. Where eligibility could not be determined, a second author assessed the full paper. One author used a standardised data extraction sheet to collect information on the studies and independently assess the quality of the studies using the validated five-point Oxford Quality Scale. The small sample sizes and differences in patient study populations of the three included studies (two from the original review and a third included in this update) prevented meta-analysis. For the original review the search strategy identified 37 possible published studies; we divided these between two pairs of review authors who decided on study selection; all four review authors discussed and agreed final scores. MAIN RESULTS: Only one additional RCT met the eligibility criteria (24 participants) for this updated review. Although this was a feasibility study, not designed to investigate intervention effect, it suggested that TENS may improve bone pain on movement in a cancer population. The initial review identified two RCTs (64 participants) therefore this review now includes a total of three RCTs (88 participants). These studies were heterogenous with respect to study population, sample size, study design, methodological quality, mode of TENS, treatment duration, method of administration and outcome measures used. In one RCT, there were no significant differences between TENS and placebo in women with chronic pain secondary to breast cancer treatment. In the other RCT, there were no significant differences between acupuncture-type TENS and sham in palliative care patients; this study was underpowered. AUTHORS' CONCLUSIONS: Despite the one additional RCT, the results of this updated systematic review remain inconclusive due to a lack of suitable RCTs. Large multi-centre RCTs are required to assess the value of TENS in the management of cancer-related pain in adults.

Efficacy and safety of combined prolonged-release oxycodone and naloxone in the management of moderate/severe chronic non-malignant pain: results of a prospectively designed pooled analysis of two randomised, double-blind clinical trials.

BACKGROUND: Two randomised 12-week, double-blind, parallel-group, multicenter studies comparing oxycodone PR/naloxone PR and oxycodone PR alone on symptoms of opioid-induced bowel dysfunction in patients with moderate/severe non-malignant pain have been conducted. METHODS: These studies were prospectively designed to be pooled and the primary outcome measure of the pooled data analysis was to demonstrate non-inferiority in 12-week analgesic efficacy of oxycodone PR/naloxone PR versus oxycodone PR alone. Patients with opioid-induced constipation were switched to oxycodone PR and then randomised to fixed doses of oxycodone PR/naloxone PR (n = 292) or oxycodone PR (n = 295) for 12 weeks (20-80 mg/day). RESULTS: No statistically significant differences in analgesic efficacy were observed for the two treatments (p = 0.3197; non-inferiority p < 0.0001; 95% CI -0.07, 0.23) and there was no statistically significant difference in frequency of analgesic rescue medication use. Improvements in Bowel Function Index score were observed for oxycodone PR/naloxone PR by Week 1 and at every subsequent time point (-15.1; p < 0.0001; 95% CI -17.3, -13.0). AE incidence was similar for both groups (61.0% and 57.3% of patients with oxycodone PR/naloxone PR and oxycodone PR alone, respectively). CONCLUSIONS: Results of this pooled analysis confirm that oxycodone PR/naloxone PR provides effective analgesia and suggest that oxycodone PR/naloxone PR improves bowel function without compromising analgesic efficacy. TRIAL REGISTRATION NUMBERS: ClinicalTrials.gov identifier: NCT00412100 and NCT00412152.

Can chronic neuropathic pain following thoracic surgery be predicted during the postoperative period?

Chronic pain following thoracic surgery is common and associated with neuropathic symptoms, however, the proportion of patients with neuropathic pain in the immediate postoperative period is unknown. We aimed to determine the proportion of patients who have neuropathic symptoms and signs immediately after, and at three months following thoracic surgery. The study was designed as a prospective observational cohort study. We identified patients with pain of predominantly neuropathic origin using the Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) score in the immediate postoperative period and the self-report LANSS (S-LANSS) version three months after surgery. One hundred patients undergoing video assisted thoracic surgery (VATS) or thoracotomy completed LANSS scores preoperatively and in the immediate postoperative period. Eighty-seven percent completed three months S-LANSS follow-up scores. Eight percent of patients had positive LANSS scores in the immediate postoperative period; 22% of patients had positive S-LANSS scores three months following surgery. There was a significant association between positive scores in the acute and chronic periods (relative risk (RR) 3.5, [95% confidence interval (CI) 1.7-7.2]). Identifying pain of predominantly neuropathic origin in the postoperative period with a simple pain score can help identify those at risk of developing chronic pain with these features following thoracic surgery.

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.

A cochrane systematic review of transcutaneous electrical nerve stimulation for cancer pain.

Cancer-related pain is complex and multi-dimensional; yet, the mainstay of cancer pain management has been the biomedical approach. There is a need for nonpharmacological and innovative pain management strategies. Transcutaneous electrical nerve stimulation (TENS) may have a role. The aim of this systematic review was to determine the effectiveness of TENS for cancer-related pain in adults. The Cochrane Library, MEDLINE, EMBASE, CINAHL, PsychINFO, AMED, and PEDro databases were searched for randomized controlled trials (RCTs) investigating the use of TENS for the management of cancer-related pain in adults. Once relevant studies were identified, two pairs of reviewers assessed eligibility for inclusion in the review based on a study eligibility form and using the 5-point Oxford Quality Scale. Two RCTs met the study eligibility criteria (these involved 64 patients). These studies were heterogeneous with respect to study population, methodology, and outcome measures. This prevented meta-analysis. In one RCT, there were no significant differences between TENS and placebo in women with chronic pain secondary to breast cancer treatment. In the other RCT, there were no significant differences between acupuncture-like TENS (AL-TENS) and sham in palliative care patients; this study was significantly underpowered. There is insufficient available evidence to determine the effectiveness of TENS in treating cancer-related pain. Further research is needed to help guide clinical practice, and large multi-center RCTs are required to assess the value of TENS in the management of cancer-related pain in adults.

Intrathecal drug delivery for management of cancer and noncancer pain.

Intrathecal drug delivery (ITDD) has been an option for the management of persistent pain since the 1980s. The discovery of opioid receptors in the central nervous system was the impetus for early attempts to deliver opioids intraspinally. Approximately, 10-20 percent patients with cancer pain get inadequate analgesia from conventional medical management; this group particularly may benefit from ITDD. However, there is also some evidence for the use of ITDD in those with noncancer pain. This review presents options for ITDD, available drugs, evidence for efficacy, principles of patient selection, and problems with the intrathecal route.

Predicting long-term response to strong opioids in patients with low back pain: findings from a randomized, controlled trial of transdermal fentanyl and morphine.

BACKGROUND: Some patients with long-standing low back pain will benefit from treatment with strong opioids. However, it would be helpful to predict which patients will have a good response. A fixed-term opioid trial has been recommended, but there is little evidence to suggest how long this trial should be. We assessed data from a large-scale randomized comparison of transdermal fentanyl (TDF) and sustained-release oral morphine (slow-release morphine; SRM) to determine characteristics of treatment responders. METHODS: This was a secondary analysis of a previously published 13-month randomized trial involving 680 patients with long-standing low back pain (median age 52 years, 61% women, median duration of back pain 87 months). Pain relief was recorded using visual analogue scales (VAS). Treatment response was defined as pain relief of at least 30% from baseline to any point during the trial. We used a step-wise logistic regression to identify variables that might predict response to treatment. Covariates included treatment group, sex, age, duration of pain, presence of neuropathic pain, baseline pain scores, educational/employment status, use of high doses of opioids, and social functioning (SF)-36 scores. RESULTS: Over half the patients in both groups (n = 370; 54% TDF, 55% SRM) were treatment responders. There were no differences between the TDF and SRM responders in terms of age, sex, type or duration of pain between responders and non-responders. The difference in response to treatment between responders and non-responders could be detected at 3 weeks. Lack of response after 1 month had a stronger negative predictive value (i.e., ability to detect non-responders) than the presence of response after 1 month. The most influential factors for predicting a response were employment status (chi2 = 11.06, p = 0.0259) and use of high doses of opioids (chi2 = 3.04, p = 0.0811). CONCLUSION: No clear pattern of baseline pain (type or severity) or patient characteristics emerged that could be used to predict responders before the start of opioid treatment. However, a 1-month trial period appears sufficient to determine response and tolerability in most cases.

Spinal cord stimulation in a patient with persistent oesophageal pain.

This study describes a man with a long history of oesophageal pain that led to inability to swallow food and drink. Over a period of 8 years, he had multiple oesophageal operations that were unsuccessful. He presented, to the pain management team, with persistent oesophageal pain and required jejunostomy tube feeding to maintain nutrition. Conservative pain management strategies failed. Spinal cord stimulation (SCS) was suggested, and after counseling, an electrode was placed in the high thoracic region. Stimulation covered the area of the chest pain. He achieved immediate reduced pain on swallowing water. A permanent system was implanted. In this case, SCS resulted in a significant improvement in pain on swallowing liquids. The patient can now also eat certain foods occasionally and enjoy the social aspect of eating; this was impossible previously. He feels that SCS has been worthwhile. The authors discuss the rationale for this treatment. The decision was based on the use of SCS for refractory angina, and the idea that the neural mechanisms that generate both these pain states may be similar.

A randomized, double-blind, crossover study of the use of transcutaneous spinal electroanalgesia in patients with pain from chronic critical limb ischemia.

Transcutaneous spinal electroanalgesia (TSE) uses two electrodes placed over the skin of the dorsal spine to deliver pulses of short wavelength, high frequency, and relatively high voltage to the spinal cord without causing paresthesia. TSE has been used to treat pain and may improve limb blood flow. This randomized, double-blind, crossover study assessed the effect of TSE on microcirculation, pain, and activity in 8 patients (3 men, 5 women, median age 66.5 years, range 62-76 years) with chronic critical limb ischemia (CLI). After a one-week baseline period, patients used an active or inactive TSE machine for one hour daily for one week. Following a week of no stimulation, patients repeated the week of treatment with an identical matched machine. Daily use of TSE for one week did not improve microcirculatory perfusion (transcutaneous oxygenation), pain (verbal rating scale, McGill Pain Questionnaire), physical function (Functional Limitations Profile), mood (Beck Depression Inventory, Beck Anxiety Inventory), or sleep. There was no patient preference for the active TSE machines. This study showed that TSE administered daily for one week did not improve microcirculation, pain, or activity in patients with chronic CLI.

Gabapentin in the treatment of neuropathic pain.

This paper reviews the pharmacology and clinical effectiveness of gabapentin in the treatment of neuropathic pain. Gabapentin has antihyperalgesic and antiallodynic properties but does not have significant actions as an anti-nociceptive agent. Its mechanisms of action appear to be a complex synergy between increased GABA synthesis, non-NMDA receptor antagonism and binding to the alpha2delta subunit of voltage dependent calcium channels. The latter action inhibits the release of excitatory neurotransmitters. Clinically, several large randomized controlled trials have demonstrated its effectiveness in the treatment of a variety of neuropathic pain syndromes. Patients with neuropathic pain can expect a mean reduction in pain score of 2.05 points on an 11 point numerical rating scale compared with a reduction of 0.94 points if they had taken the placebo. Around 30% of patients can expect to achieve more than 50% pain relief and a similar number will also experience minor adverse events; the most common of which are somnolence and dizziness. In patients with neuropathic pain due to cancer, higher response rates might be observed with gabapentin when administered with opioids because of a synergistic interaction.