Association of opioid prescribing practices with chronic pain and benzodiazepine co-prescription: a primary care data linkage study.

BACKGROUND: Opioid prescribing is increasing worldwide with associated increases in misuse and other harms. We studied variations in national opioid prescription rates, indicators of prescribing quality, co-prescribing of benzodiazepines and relationship with pain severity in Scotland. METHODS: Electronic linkages of opioid prescribing in Scotland were determined from: (i) national data from Information Services Division, NHS Scotland (2003-2012); and (ii) individual data from Generation Scotland: Scottish Family Health Study. Descriptive analyses were conducted on national data, multilevel modelling to examine factors associated with variations in prescribing rates. χ2 tests examined associations between individual pain severity and opioid prescriptions. RESULTS: The number of strong opioid prescriptions more than doubled from 474 385 in 2003 to 1 036 446 in 2012, and weak opioid prescribing increased from 3 261 547 to 4 852 583. In Scotland, 938 674 individuals were prescribed an opioid in 2012 (18% of the population). Patients in the most deprived areas were 3.5 times more likely to receive a strong opioid than patients in the least deprived. There was significant variation in prescribing rates between geographical areas, with much of this explained by deprivation. Of women aged 25-40 yr prescribed a strong opioid, 40% were also prescribed a benzodiazepine. There was significant association between pain severity and receipt of opioid prescription. Over 50% of people reporting severe pain were not prescribed an opioid analgesic. CONCLUSIONS: We found opioid prescribing in primary care to be common and increasing in Scotland, particularly for severe pain. Co-prescribing of opioids and benzodiazepines was common.

A multicentre, open-label, follow-on study to assess the long-term maintenance of effect, tolerance and safety of THC/CBD oromucosal spray in the management of neuropathic pain.

Peripheral neuropathic pain (PNP) poses a significant clinical challenge. The long-term efficacy of delta-9-tetrahydrocannabinol (THC)/cannabidiol (CBD) oromucosal spray was investigated in this 38-week open-label extension study. In total, 380 patients with PNP associated with diabetes or allodynia entered this study from two parent randomised, controlled trials. Patients received THC/CBD spray for a further 38 weeks in addition to their current analgesic therapy. Neuropathic pain severity was the primary efficacy measure using a pain 0-10 numerical rating scale (NRS). Additional efficacy, safety and tolerability outcomes were also investigated. In total, 234 patients completed the study (62 %). The pain NRS showed a decrease in score over time in patients from a mean of 6.9 points (baseline in the parent studies) to a mean of 4.2 points (end of open-label follow-up). The proportion of patients who reported at least a clinically relevant 30 % improvement in pain continued to increase with time (up to 9 months); at least half of all patients reported a 30 % improvement at all time points. Improvements were observed for all secondary efficacy outcomes, including sleep quality 0-10 NRS scores, neuropathic pain scale scores, subject global impression of change and EQ-5D questionnaire scores. THC/CBD spray was well tolerated for the study duration and patients did not seek to increase their dose with time, with no new safety concerns arising from long-term use. In this previously difficult to manage patient population, THC/CBD spray was beneficial for the majority of patients with PNP associated with diabetes or allodynia.

A double-blind, randomized, placebo-controlled, parallel group study of THC/CBD spray in peripheral neuropathic pain treatment.

BACKGROUND: Peripheral neuropathic pain (PNP) associated with allodynia poses a significant clinical challenge. The efficacy of Δ(9) -tetrahydrocannabinol/cannabidiol (THC/CBD) oromucosal spray, a novel cannabinoid formulation, was investigated in this 15-week randomized, double-blind, placebo-controlled parallel group study. METHODS: In total, 303 patients with PNP associated with allodynia were screened; 128 were randomized to THC/CBD spray and 118 to placebo, in addition to their current analgesic therapy. The co-primary efficacy endpoints were the 30% responder rate in PNP 0-10 numerical rating scale (NRS) score and the mean change from baseline to the end of treatment in this score. Various key secondary measures of pain and functioning were also investigated. RESULTS: At the 30% responder level, there were statistically significant treatment differences in favour of THC/CBD spray in the full analysis (intention-to-treat) dataset [p = 0.034; 95% confidence interval (CI): 1.05-3.70]. There was also a reduction in mean PNP 0-10 NRS scores in both treatment groups that was numerically higher in the THC/CBD spray group, but which failed to reach statistical significance. Secondary measures of sleep quality 0-10 NRS score (p = 0.0072) and Subject Global Impression of Change (SGIC) (p = 0.023) also demonstrated statistically significant treatment differences in favour of THC/CBD spray treatment. CONCLUSIONS: These findings demonstrate that, in a meaningful proportion of otherwise treatment-resistant patients, clinically important improvements in pain, sleep quality and SGIC of the severity of their condition are obtained with THC/CBD spray. THC/CBD spray was well tolerated and no new safety concerns were identified.

Pregabalin in the treatment of post-traumatic peripheral neuropathic pain: a randomized double-blind trial.

BACKGROUND: Pregabalin is effective in the treatment of peripheral and central neuropathic pain. This study evaluated pregabalin in the treatment of post-traumatic peripheral neuropathic pain (including post-surgical). METHODS: Patients with a pain score >or=4 (0-10 scale) were randomized and treated with either flexible-dose pregabalin 150-600 mg/day (n = 127) or placebo (n = 127) in an 8-week double-blind treatment period preceded by a 2-week placebo run-in. RESULTS: Pregabalin was associated with a significantly greater improvement in the mean end-point pain score vs. placebo; mean treatment difference was -0.62 (95% CI -1.09 to -0.15) (P = 0.01). The average pregabalin dose at end-point was approximately 326 mg/day. Pregabalin was also associated with significant improvements from baseline in pain-related sleep interference, and the Medical Outcomes Study sleep scale sleep problems index and sleep disturbance subscale (all P < 0.001). In the all-patient group (ITT), pregabalin was associated with a statistically significant improvement in the Hospital Anxiety and Depression Scale anxiety subscale (P < 0.05). In total, 29% of patients had moderate/severe baseline anxiety; treatment with pregabalin in this subset did not significantly improve anxiety. More patients reported global improvement at end-point with pregabalin than with placebo (68% vs. 43%; overall P < 0.01). Adverse events led to discontinuation of 20% of patients from pregabalin and 7% from placebo. Mild or moderate dizziness and somnolence were the most common adverse events in the pregabalin group. CONCLUSION: Flexible-dose pregabalin 150-600 mg/day was effective in relieving neuropathic pain, improving disturbed sleep, improving overall patient status, and was generally well tolerated in patients with post-traumatic peripheral neuropathic pain.

Perioperative haemodynamic changes in patients undergoing laparoscopic adrenalectomy for phaeochromocytomas and other adrenal tumours.

BACKGROUND: Perioperative haemodynamic changes are well recognised sequelae of adrenalectomy for phaeochromocytomas. The aim of this study was to compare haemodynamic changes in patients undergoing laparoscopic adrenalectomy (LA) for phaeochromocytomas and other adrenal tumours. METHOD: Patients were identified from a prospective database (Jan 1999-Feb 2008). All patients were managed by a multi-disciplinary team. Haemodynamic variables were: pulse, blood pressure and the requirement of antihypertensive or vasopressor therapies in the perioperative period. RESULTS: Over the nine-year period, 34 consecutive patients underwent laparoscopic phaeochromocytoma resection (one patient had delayed contralateral LA) and 104 consecutive patients underwent LA for other tumours (two patients had delayed contralateral LA). 5 out of 35 resections in the phaeochromocytoma group experienced severe hypertension (systolic blood pressure (SBP) >200 mm Hg) compared to two out of 106 resections in the non phaeochromocytoma group (p=0.010). No patient in either group had a transient or persistent (>10 min) SBP >220 mm Hg. Intraoperative antihypertensive use was significantly increased in the phaeochromocytoma group (p<0.005). There were no significant differences between groups for persistent hypotension (SBP <80 mm Hg), heart rate >120/min and recovery room haemodynamic parameters. CONCLUSION: LA for phaeochromocytoma can be accomplished with low perioperative haemodynamic complications when compared to LA for other adrenal tumours.

Comparison of analgesic effects and patient tolerability of nabilone and dihydrocodeine for chronic neuropathic pain: randomised, crossover, double blind study.

OBJECTIVE: To compare the analgesic efficacy and side effects of the synthetic cannabinoid nabilone with those of the weak opioid dihydrocodeine for chronic neuropathic pain. DESIGN: Randomised, double blind, crossover trial of 14 weeks' duration comparing dihydrocodeine and nabilone. SETTING: Outpatient units of three hospitals in the United Kingdom. PARTICIPANTS: 96 patients with chronic neuropathic pain, aged 23-84 years. MAIN OUTCOME MEASURES: The primary outcome was difference between nabilone and dihydrocodeine in pain, as measured by the mean visual analogue score computed over the last 2 weeks of each treatment period. Secondary outcomes were changes in mood, quality of life, sleep, and psychometric function. Side effects were measured by a questionnaire. INTERVENTION: Patients received a maximum daily dose of 240 mg dihydrocodeine or 2 mg nabilone at the end of each escalating treatment period of 6 weeks. Treatment periods were separated by a 2 week washout period. Results Mean baseline visual analogue score was 69.6 mm (range 29.4-95.2) on a 0-100 mm scale. 73 patients were included in the available case analysis and 64 patients in the per protocol analysis. The mean score was 6.0 mm longer for nabilone than for dihydrocodeine (95% confidence interval 1.4 to 10.5) in the available case analysis and 5.6 mm (10.3 to 0.8) in the per protocol analysis. Side effects were more frequent with nabilone. CONCLUSION: Dihydrocodeine provided better pain relief than the synthetic cannabinoid nabilone and had slightly fewer side effects, although no major adverse events occurred for either drug. TRIAL REGISTRATION: Current Controlled Trials ISRCTN15330757 controlled-trials.com] .

Laparoscopic colonic resection in fast-track patients does not enhance short-term recovery after elective surgery.

BACKGROUND: Laparoscopic colorectal surgery has been claimed to enhance recovery when compared with open surgery. The aim of our study was to investigate whether laparoscopic colorectal resection improved recovery with the use of a multimodal rehabilitation programme. METHOD: We carried out a prospective audit of 80 patients undergoing elective colorectal resection between November 2003 and March 2005. All patients underwent a fast-track protocol with early feeding, mobilization and a fluid and sodium restriction regime. Recovery was measured in terms of return of gastrointestinal function, hospital stay, complications and quality of life measures. RESULTS: Of the 80 patients in the study 22 underwent laparoscopic resection and 58 had open surgery. Patients were well matched for all baseline characteristics. The groups were not significantly different in terms of opioid or antiemetic use. They were also similar in median time to first flatus (69 h vs 69 h, P = 0.36) and median time to first bowel motion (127 h vs 101 h, P = 0.07). There was no difference in median hospital stay (5.8 days vs 5.9 days, P = 0.87) or complications (P = 0.46) between the laparoscopic and open group. There were no significant differences in Short Form 36 scores between the two groups for any of the components measured. CONCLUSION: Laparoscopic colorectal resection does not appear to reduce the duration of ileus or hospital stay with the use of a multimodal rehabilitation regime. Further large randomized trials are required to confirm these findings.

Randomized clinical trial of the effect of postoperative intravenous fluid restriction on recovery after elective colorectal surgery.

BACKGROUND: Use of intravenous fluids is an important part of perioperative management. The aim of this study was to compare outcome following administration of restricted or standard postoperative intravenous fluids and sodium in patients undergoing elective colorectal surgery. METHODS: Eighty patients were randomized to restricted fluids (less than 2 litres water and 77 mmol sodium for 24 h after surgery) or a standard postoperative fluid regimen (3 litres water and 154 mmol sodium per day for as long as necessary). The primary endpoint was hospital stay. RESULTS: The median (i.q.r.) total intravenous fluid intake in the restricted group was 4.50 (4.00-5.62) litres compared with 8.75 (8.00-9.80) litres in the standard group (P < 0.001). Intravenous sodium intake was also significantly less in the restricted group (229 (131-332) versus 560 (477-667) mmol; P < 0.001). There was no difference in median time to first flatus (2.9 versus 2.9 days; hazard ratio (HR) 0.85 (95 per cent confidence interval (c.i.) 0.54 to 1.32); P = 0.466) or first bowel motion (4.7 versus 4.9 days; HR 1.06 (95 per cent c.i. 0.68 to 1.65); P = 0.802) between the restricted and standard groups, or in median hospital stay (7.2 versus 7.2 days; HR 1.03 (95 per cent c.i. 0.66 to 1.61); P = 0.902). CONCLUSION: Restriction of postoperative intravenous fluid and sodium does not reduce hospital stay following elective colorectal surgery.

Anaesthesia for cholecystectomy in two non-parturients with Eisenmenger's syndrome.

Eisenmenger's syndrome consists of high pulmonary vascular resistance with reversed or bidirectional shunt at aortopulmonary, ventricular or atrial level. We describe the anaesthetic management of two adult females with Eisenmenger's syndrome admitted for laparoscopic cholecystectomy. One patient suffered post-operative complications, but the other case was uncomplicated. We used sevoflurane and total intravenous anaesthesia to provide general anaesthesia. Both techniques were tolerated.

Gabapentin in neuropathic pain syndromes: a randomised, double-blind, placebo-controlled trial.

A double-blind, randomised, placebo-controlled 8-week study was conducted to evaluate the efficacy and safety of gabapentin in the treatment of neuropathic pain, using doses up to 2400 mg/day. The study used a novel design that was symptom- rather than syndrome-based; an approach that aimed to reflect the realities of clinical practice. Participants had a wide range of neuropathic pain syndromes, with at least two of the following symptoms: allodynia, burning pain, shooting pain, or hyperalgesia. Patients were randomised to gabapentin (n=153) or placebo (n=152). Gabapentin was given in three divided doses, initially titrated to 900 mg/day over 3 days, followed by two further increases, to a maximum of 2400 mg/day if required by the end of week 5. The primary outcome measure was changed in average daily pain diary score (baseline versus final week). Over the 8 week study, this score decreased (i.e. improved) by 1.5 (21%) in gabapentin treated patients and by 1.0 (14%) in placebo treated patients (P=0.048, rank-based analysis of covariance). Significant differences were shown in favour of gabapentin (P<0.05) for the Clinician and Patient Global Impression of Change, and some domains of the Short Form-McGill Pain Questionnaire. Improvements were also shown in patient-reported outcomes in quality of life, as seen by significant differences in favour of gabapentin in several domains of the Short-Form-36 Health Survey. Gabapentin was well tolerated and the majority of patients completed the study (79 versus 73% for placebo). The most common adverse events were mild to moderate dizziness and somnolence, most of which were transient and occurred during the titration phase. This study shows that gabapentin reduces pain and improves some quality-of-life measures in patients with a wide range of neuropathic pain syndromes.

Outcome of patients with severe chronic pain following repair of groin hernia.

BACKGROUND: Chronic pain is the most serious long-term complication that can occur after repair of a groin hernia. The aim of this study was to assess the outcome of patients who report severe or very severe pain 3 months after groin hernia repair. METHODS: This was a population-based study of all patients who underwent repair of a groin hernia between April 1998 and March 1999 in Scotland. All received a postal questionnaire 3 months after hernia repair and those who reported severe or very severe pain at the operation site were asked to complete a further questionnaire 2.5 years later. The main outcome measure included the number of patients with persistent pain and the effect of pain on daily activities and quality of life. RESULTS: Of 5506 patients who underwent repair of a groin hernia, 4062 (74 per cent) returned the first questionnaire and 125 (3 per cent) reported severe or very severe pain. Eight-six (72 per cent) of 120 patients (five had died or could not be contacted at the original address) replied to the second questionnaire; 61 (71 per cent) still reported pain, which was severe or very severe pain in 22 (26 per cent) and mild or very mild in 39 (45 per cent). Twenty-nine (48 per cent) sought further medical help from their general practitioner or surgeon. Nine (15 per cent) attended a pain clinic while five (8 per cent) had further surgery. Chronic pain had significant effects (P < 0.001) on all daily activities including walking, work, sleep, relationships with other people, mood and general enjoyment of life. CONCLUSION: Chronic pain persists in most patients who report severe or very severe pain at 3 months after hernia repair, and has a significant effect on the patients' daily activities and quality of life.

Rate of injection through whitacre needles affects distribution of spinal anaesthesia.

A prospective, randomized, double-blind study was performed to investigate whether altering the rate of injection of local anaesthetic through a Whitacre needle had any effect on the spinal block achieved. Twenty patients scheduled for elective urological surgery under spinal anaesthesia received an injection of 3 ml of 0.5% plain bupivacaine either by hand (fast) over 10 s (18 ml min(-1)) or by infusion pump (slow) over 3 min (1 ml min(-1)). All patients were in the sitting position both during insertion of the spinal needle and for 3 min after the start of spinal injection, and they then changed to the supine position. The slow injection group achieved peak sensory block earlier, after a median interval of 20 (95% confidence interval 12.5-30) min vs 30 (22.5-45) min (P<0.05) for the fast group. The level of peak sensory block was similar: T3.5 (T2-T4.5) vs T4 (T1.5-T6.5). The time to lowest mean arterial pressure occurred earlier in the slow group, at 10 (8 to 18) vs 20 (15-31) min (P<0.05). Duration of the motor block was shorter in the slow group: 180 (152-242) vs 270 (225-300). We conclude that a slow spinal injection of plain bupivacaine results in a block of more rapid onset and recovery.

I.v. regional diamorphine for analgesia after foot surgery.

Opioids administered to peripheral tissues can have significant analgesic effects in doses which would not be effective centrally. We have assessed the effects of regional diamorphine 2.5 mg i.v. in 14 patients undergoing surgical correction of bilateral arthritic foot deformities in a prospective, randomized, double-blind study. Patients acted as their own controls as only one foot received the active drug. Visual analogue scale (VAS) pain scores and wound tenderness were measured over 72 h. Diamorphine did not improve median VAS area under the curve pain scores during the first 6 h after surgery (33 (95% confidence intervals (CI) 25-46) vs 24 (17-35)). It also did not effect wound hypersensitivity when tested at 72 h after surgery (95 (47-125) vs 90 (50-125) g). There were no significant adverse effects.

Intrathecal anesthesia with ketamine.

BACKGROUND AND OBJECTIVES: Intrathecal anesthesia is the method of choice for transurethral prostate resection in the United Kingdom, despite its associated hypotension. Intrathecal ketamine with epinephrine has been used for lower limb surgery with minimal cardiovascular disturbance. Because cardiovascular stability might be advantageous in this group of elderly patients, we undertook this study to determine if intrathecal ketamine was a suitable intrathecal anesthetic agent for transurethral prostate surgery. Because of the high incidence of side effects and inadequate analgesia, the study was terminated after only ten patients had been recruited. METHODS: Ten ASA I to III males were studied. Spinal anesthesia was performed with a 25-gauge Whitacre needle at the L2-L3 or L3-L4 space. The dose of ketamine was determined by a sequential allocation technique after initial empirical doses of 0.5 and 0.75 mg/kg. Sensory and motor block were monitored using pinprick and modified Bromage score, respectively. If spinal anesthesia was inadequate at any time, a general anesthetic was administered. RESULTS: At doses higher than 0.7 mg/kg, intrathecal ketamine produced both motor and sensory block. The onset of motor block was within 2-3 minutes, peaked in 5-10 minutes, and lasted 30-60 minutes. Sensory block took 5-20 minutes to reach its maximal height. Maximum sensory block height varied from L1 to T7. Despite adequate block to pinprick, half the patients sensed the diathermy and were given a general anesthetic. The incidence of severe psychotomimetic side effects was 30%. CONCLUSIONS: Intrathecal ketamine at doses of 0.7-0.95 mg/kg produces sensory and motor block. The frequency of psychomimetic disturbance, inadequate analgesia, and short duration of action preclude its use as a sole anesthetic agent.

Malignant hyperthermia during prolonged surgery for tumour resection.

The onset of malignant hyperthermia in a patient during a prolonged anaesthetic for tumour resection is described. The onset was delayed with a gradual rise in heart rate and PETCO2 before becoming fulminant; muscle rigidity was not a feature. Other aspects of the patient's condition confused the presentation, delayed the diagnosis and may have been involved in precipitating the event. However, it responded rapidly to treatment and surgery was continued. A possible recrudescence occurred 18 h later. Malignant hyperthermia should be considered early in cases of unexplained tachycardia or rising PETCO2.

Randomized trial of different insufflation pressures for laparoscopic cholecystectomy.

BACKGROUND: The factors affecting cardiorespiratory changes and postoperative pain after laparoscopic cholecystectomy are poorly understood. The aim of this study was to assess these changes in patients undergoing laparoscopic cholecystectomy at an insufflation pressure of 7.5 or 15 mmHg. METHODS: Forty patients with similar preoperative characteristics were randomized, 20 to each group. RESULTS: There were no significant differences in intraoperative heart rate or cardiac index although the latter fell significantly soon after insufflation in both groups. The fall in cardiac index lasted longer (7 versus 2 min) and coincided with a slower rise in mean arterial pressure in those having 15 mmHg insufflation. Changes in peak airway pressure, end-tidal carbon dioxide and arterial blood gases were similar. After operation the low-pressure group had significantly less pain, better preservation of pulmonary function and were discharged home sooner (P = 0.015). CONCLUSIONS: Insufflation pressure significantly affects the haemodynamic changes and postoperative pain associated with laparoscopic cholecystectomy.

Flow dynamics through spinal needles.

We examined the flow pattern produced when liquid dye was actively injected into a fluid medium at various flows through five different commonly used spinal needles. At all flows, the Whitacre-type needles produced a directional stream exiting at an angle from the longitudinal axis. At intermediate rates the stream developed tracks which disappeared at faster rates. The Quincke needle always produced an undeviated stream of dye and did not form tracks at any flow rate. When a perspex plate (representing the spinal cord) was interposed in front of the needle, the dispersion of dye was always unidirectional from the Whitacre needle and bidirectional from the Quincke needle. The dye adhered to the surface of the plate as a concentrated film at slow rates and at faster rates it dispersed turbulently for both types of needle.