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.

Clinical and preclinical perspectives on Chemotherapy-Induced Peripheral Neuropathy (CIPN): a narrative review.

This review provides an update on the current clinical and preclinical understanding of chemotherapy induced peripheral neuropathy (CIPN). The overview of the clinical syndrome includes a review of its assessment, diagnosis and treatment. CIPN is caused by several widely-used chemotherapeutics including paclitaxel, oxaliplatin, bortezomib. Severe CIPN may require dose reduction, or cessation, of chemotherapy, impacting on patient survival. While CIPN often resolves after chemotherapy, around 30% of patients will have persistent problems, impacting on function and quality of life. Early assessment and diagnosis is important, and we discuss tools developed for this purpose. There are no effective strategies to prevent CIPN, with limited evidence of effective drugs for treating established CIPN. Duloxetine has moderate evidence, with extrapolation from other neuropathic pain states generally being used to direct treatment options for CIPN. The preclinical perspective includes a discussion on the development of clinically-relevant rodent models of CIPN and some of the potentially modifiable mechanisms that have been identified using these models. We focus on the role of mitochondrial dysfunction, oxidative stress, immune cells and changes in ion channels from summary of the latest literature in these areas. Many causal mechanisms of CIPN occur simultaneously and/or can reinforce each other. Thus, combination therapies may well be required for most effective management. More effective treatment of CIPN will require closer links between oncology and pain management clinical teams to ensure CIPN patients are effectively monitored. Furthermore, continued close collaboration between clinical and preclinical research will facilitate the development of novel treatments for CIPN.

Systematic review to determine which validated measurement tools can be used to assess risk of problematic analgesic use in patients with chronic pain.

Background: Misuse of prescription opioids, and other drugs prescribed for chronic pain, has increased, with major concerns about harm. This review was undertaken to identify validated measurement tools for risk assessment and monitoring of chronic non-cancer pain patients being considered for, or currently prescribed, analgesic drugs with abuse potential. Methods: Selected databases (Embase, Medline, Cochrane library/CENTRAL, PsycINFO, PubMed, CINAHL) were systematically searched for studies evaluating tools for risk of analgesic misuse, either before, or during, analgesic therapy for chronic pain, using predetermined inclusion/exclusion criteria. Two independent reviewers assessed abstracts, selected full texts, extracted data and assessed quality. Results: 30 studies from 1844 met inclusion criteria, including three systematic reviews, with an additional four studies from bibliography review. The studies covered 14 tools pertaining to opioid use, with none for non-opioid analgesics. Conclusions: For predicting prescription opioid misuse, the pain medication questionnaire (PMQ) and the screener and opioid assessment for patients with pain (SOAPP) had the best evidence; both developed and validated in five separate studies (four each of acceptable quality). The current opioid misuse measure (COMM) performed best screening for current misuse, developed and validated in three studies of acceptable quality. A small number of tools may accurately predict, or identify, opioid misuse. There are none for non-opioid analgesics, where there is a potential need.

MitoVitE, a mitochondria-targeted antioxidant, limits paclitaxel-induced oxidative stress and mitochondrial damage in vitro, and paclitaxel-induced mechanical hypersensitivity in a rat pain model.

BACKGROUND: Neuropathic pain is a common side-effect of chemotherapy. Although precise mechanisms are unclear, oxidative stress and mitochondrial damage are involved. We investigated whether the mitochondria targeted antioxidant, MitoVitE, provided better protection against paclitaxel-induced mitochondrial damage in rat dorsal root ganglion (DRG) cells, than a non-targeted form of vitamin E, Trolox. We also determined whether MitoVitE, compared with duloxetine, could limit paclitaxel-induced mechanical hypersensitivity in rats. METHODS: Mitochondrial function was measured in DRG cells exposed to paclitaxel with and without MitoVitE or Trolox. The effect of MitoVitE or Trolox on paclitaxel-induced cell killing in cancer cell lines was also determined. Rats received a cumulative dose of 8 mg kg-1 paclitaxel plus either MitoVitE (2 mg-1 kg day-1), duloxetine (10 mg kg-1 day-1) or vehicle control daily. Mechanical hind paw withdrawal thresholds were measured every two days. RESULTS: Paclitaxel caused loss of membrane potential in DRG cells. At 100 µM paclitaxel median [range] change was 61[44-78]%, P < 0.0001, which was ameliorated by MitoVitE (86[62-104]%) but not Trolox (46[46-57]%). Similarly, loss of metabolic activity and glutathione induced by paclitaxel (both P < 0.0001) were reduced by MitoVitE but not Trolox. Cytotoxicity of paclitaxel was not affected by co-exposure of ovarian cancer cells to either MitoVitE or Trolox, but was slightly reduced against breast cancer cells, in the presence of Trolox. Mean (SD) areas under the curve of withdrawal thresholds at 6 h after injection in rats given paclitaxel + control, or + MitoVitE (P < 0.0001) or + duloxetine (P < 0.0001) were 110 (5), 145 (10) and 156 (13) respectively. CONCLUSIONS: Paclitaxel affected mitochondrial function and glutathione in DRG cells, which was abrogated by MitoVitE but not Trolox, without decreasing cancer cell cytotoxicity. In rats, paclitaxel-induced mechanical hypersensitivity was ameliorated by MitoVitE treatment to an extent similar to duloxetine. These data confirm mitochondria as a mechanistic target for paclitaxel-induced damage and suggest mitochondria targeted antioxidants as future therapeutic strategies.

Pain management in patients with vascular disease.

Vascular disease covers a wide range of conditions, including arterial, venous, and lymphatic disorders, with many of these being more common in the elderly. As the population ages, the incidence of vascular disease will increase, with a consequent increase in the requirement to manage both acute and chronic pain in this patient population. Pain management can be complex, as there are often multiple co-morbidities to be considered. An understanding of the underlying pain mechanisms is helpful in the logical direction of treatment, particularly in chronic pain states, such as phantom limb pain or complex regional pain syndrome. Acute pain management for vascular surgery presents a number of challenges, including coexisting anticoagulant medication, that may preclude the use of regional techniques. Within the limited evidence base, there is a suggestion that epidural analgesia provides better pain relief and reduced respiratory complications after major vascular surgery. For carotid endarterectomy, there is again some evidence supporting the use of local anaesthetic analgesia, either by infiltration or by superficial cervical plexus block. Chronic pain in vascular disease includes post-amputation pain, for which well-known risk factors include high pain levels before amputation and in the immediate postoperative period, emphasizing the importance of good pain control in the perioperative period. Complex regional pain syndrome is another challenging chronic pain syndrome with a wide variety of treatment options available, with the strongest evidence being for physical therapies. Further research is required to gain a better understanding of the underlying pathophysiological mechanisms in pain associated with vascular disease and the best analgesic approaches to manage it.

Cancer treatment-related neuropathic pain: proof of concept study with menthol--a TRPM8 agonist.

PURPOSE: Effective treatment of neuropathic pain without unacceptable side effects is challenging. Cancer sufferers increasingly live with long-term treatment-related neuropathic pain, resulting from chemotherapy-induced peripheral neuropathy (CIPN) or surgical scars. This proof-of-concept study aimed to determine whether preclinical evidence for TRPM8 ion channels in sensory neurons as a novel analgesic target could be translated to clinical benefit in patients with neuropathic pain, using the TRPM8 activator menthol. PATIENTS AND METHODS: Patients with problematic treatment-related neuropathic pain underwent a baseline assessment using validated questionnaires, psychophysical testing, and objective functional measures. The painful area was treated with topical 1 % menthol cream twice daily. Assessments were repeated at 4-6 weeks. The primary outcome was the change in Brief Pain Inventory total scores at 4-6 weeks. Secondary outcomes included changes in function, mood and skin sensation. RESULTS: Fifty-one patients (female/male, 32/19) were recruited with a median age of 61 (ranging from 20 to 89). The commonest aetiology was CIPN (35/51), followed by scar pain (10/51). Thirty-eight were evaluable on the primary outcome. Eighty-two per cent (31/38) had an improvement in total Brief Pain Inventory scores (median, 47 (interquartile range, 30 to 64) to 34 (6 to 59), P < 0.001). Improvements in mood (P = 0.0004), catastrophising (P = 0.001), walking ability (P = 0.008) and sensation (P < 0.01) were also observed. CONCLUSION: This proof-of-concept study indicates that topical menthol has potential as a novel analgesic therapy for cancer treatment-related neuropathic pain. Improvements in patient-rated measures are supported by changes in objective measures of physical function and sensation. Further systematic evaluation of efficacy is required.

Dental admissions in children under two years--a total-population investigation.

BACKGROUND: There is a lack of literature describing dental admissions in children particularly very young children. This paper describes dental and oral cavity admissions and associated factors in children under two years of age using total-population databases. METHODS: The data used for this study were extracted from population-based databases which are linkable with midwives' data collected on all births in Western Australia. Children born from 1980 to 1998 inclusive (n = 459,831) were followed until two years of age including data on deaths, hospital admissions, birth defects and intellectual disability. Dental admissions (by ICD-9 category) and associated factors were investigated. RESULTS: There were 1513 dental admissions occurring in 1459 of the children up to the age of two years. Children were most frequently admitted under ICD-9 category 521, which includes a hospital admission for dental caries (39% of all oral cavity admissions), followed by ICD-9 category 528 (29%), which includes diseases of the oral soft tissues. Univariate analysis indicated that those with intellectual disability (OR 2.10, 95%CI 1.40-3.16), birth defect (1.74, 1.45-2.09), residing in a region without fluoridated water (2.15, 1.72-2.69) being male (1.14, 1.03-1.26), those from rural areas (2.29, 2.07-2.54) and Indigenous children (4.45, 3.91-5.05) were significantly more likely to have had a dental admission. CONCLUSION: Using total-population data allowed us to describe the admissions in children under two years and associated factors while able to identify children with intellectual disability or birth defects.

Quantitative Sensory Testing to assess the sensory characteristics of cancer-induced bone pain after radiotherapy and potential clinical biomarkers of response.

BACKGROUND/AIMS: Radiotherapy (XRT) is the gold standard treatment for cancer-induced bone pain (CIBP), but only 50% of patients achieve adequate pain relief within 6 weeks. No predictors of analgesic response to XRT are known. The aim of this preliminary study was to explore the effect of XRT on sensory changes in CIBP with a view to predicting response. METHODS: After ethics committee approval, patients with CIBP were assessed prior to and 4-6 weeks after palliative XRT. This included completion of the Brief Pain Inventory (BPI) and bedside Quantitative Sensory Testing (QST) measuring evoked sensations to quantified stimuli on the skin over the area of CIBP and a control site. RESULTS: Twenty-three patients were assessed pre and post XRT. Thirteen (57%) had an analgesic response (defined as ≥30% reduction in total BPI). Those patients who had normalisation of abnormal warm sensation ("warm responders", n = 6) were different in that they had higher baseline functional BPI pain scores (median score (IQR) in warm responders = 43 (31.75-58) compared to 31 (12-39.5) in the remaining patients, p = 0.039), larger reductions in pain scores (median difference of 33.5 in total BPI, p = 0.027) and increased likelihood of resolution of sensitivity to pinprick. CONCLUSIONS: This is the first clinical study to demonstrate alterations in sensory responses in CIBP. Alterations in specific sensory characteristics seem to be associated with an increased likelihood of successful analgesia from palliative XRT. This supports the use of QST in further biomarker studies to predict response to therapy and aid clinical decision making.

Total population investigation of dental hospitalizations in indigenous children under five years in Western Australia using linked data.

BACKGROUND: The aim of this study was to compare dental hospital admissions in a total state birth population of Indigenous and non-Indigenous children aged under five years in Western Australia. METHODS: Midwives' notification data were linked to databases of deaths, admissions, birth defects and intellectual disability. Births during 1980-1995 were followed until five years of age (n = 383,665). Dental admissions were classified by ICD-9 principal diagnosis categories. RESULTS: There were 738 dental admissions for 665 children aged up to five years of Indigenous mothers (n = 20,921). Indigenous children comprised 6.3% of all children having a dental admission in this age group; 3.2% of children with Indigenous mothers had a dental admission compared with 2.7% of non-Indigenous children. Overall, 8.7% (n = 58) of Indigenous children with a dental admission had a birth defect and 5.5% (n = 23) had an intellectual disability (compared to 8.8% and 3.2%). Indigenous children were four times more likely to be diagnosed with oral soft tissue diseases than non-Indigenous children, and less likely to be categorized as having diseases of the dental hard tissues. Indigenous children were more likely to have a longer dental admission. CONCLUSIONS: These analyses provide important findings regarding hospital admissions for Indigenous children. Admissions for disorders of the soft tissues are more common in Indigenous children.