Lesley Colvin

Prevalence and natural history of pain in adults with multiple sclerosis: Systematic review and meta-analysis

The prevalence, associations, and natural history of pain in multiple sclerosis (MS) are poorly understood. The objective of this work was to study the prevalence of pain syndromes in MS both cross‐sectionally, and longitudinally during the MS disease course. We systematically identified prospective studies detailing pain prevalence in definite MS. We used pooled prevalence estimates, explored heterogeneity using meta‐regression, and analysed prevalence during the disease course using both estimates at disease milestones and longitudinal studies. Twenty‐eight articles (7101 subjects) describing overall pain, or pain syndromes, met inclusion criteria. Pooled overall pain prevalence (17 studies, 5319 subjects) was 63% (95% confidence interval [CI] 55–70%). Marked heterogeneity in this estimate was not significantly explained by selected study design variables (use of outpatient sample, timeframe prior to study over which pain was assessed) or sample demographic variables (mean Expanded Disability Status Scale, mean disease duration, proportion of female sex, and proportion with progressive MS). We quantified prevalence of headache (43%; 95% CI 33–52%), neuropathic extremity pain (26%; 95% CI 7–53%), back pain (20%; 95% CI 13–28%), painful spasms (15%; 95% CI 8.5–23%), Lhermitte sign (16%; 95% CI 10–25%), and trigeminal neuralgia (3.8%; 95% CI 2–6%) in included studies. Prevalence of pain at MS disease milestones (prior to onset, at onset, and at relapse) and during longitudinal follow‐up was poorly described. Pain is common in MS, as are specific pain syndromes. The clinical associations and natural history of pain in MS require clarification. Future study could be enhanced by standardised study design.

A randomised double blind trial of the effect of pre-emptive epidural ketamine on persistent pain after lower limb amputation.

&NA; Persistent pain has been reported in up to 80% of patients after limb amputation. The mechanisms are not fully understood, but nerve injury during amputation is important, with evidence for the crucial involvement of the spinal N‐methyl d‐aspartate (NMDA) receptor in central changes. The study objective was to assess the effect of pre‐emptively modulating sensory input with epidural ketamine (an NMDA antagonist) on post‐amputation pain and sensory processing. The study recruited 53 patients undergoing lower limb amputation who received a combined intrathecal/epidural anaesthetic for surgery followed by a randomised epidural infusion (Group K received racemic ketamine and bupivacaine; Group S received saline and bupivacaine). Neither general anaesthesia nor opioids were used during the peri‐operative period. Pain characteristics were assessed for 12 months. The primary endpoint was incidence and severity of post‐amputation pain. Persistent pain at one year was much less in both groups than in comparable studies, with no significant difference between groups (Group K = 21% (3/14) and 50% (7/14); and Group S = 33% (5/15) and 40% (6/15) for stump and phantom pain, respectively). Post‐operative analgesia was significantly better in Group K, with reduced stump sensitivity. The intrathecal/epidural technique used, with peri‐operative sensory attenuation, may have reduced ongoing sensitisation, reducing the overall incidence of persistent pain. The improved short‐term analgesia and reduced mechanical sensitivity in Group K may reflect acute effects of ketamine on central sensitisation. Longer term effects on mood were detected in Group K that requires further study.

Pain, depression, and fatigue as a symptom cluster in advanced cancer.

CONTEXT Pain, depression, and fatigue are common symptoms in cancer populations. They often coexist and have been suggested as a specific symptom cluster. Systemic inflammation (SI) may be a possible common mechanism. OBJECTIVE This study examined whether pain, depression, and fatigue exist as a symptom cluster in advanced cancer patients with cachexia and might be related to the presence of SI. METHODS Secondary data analysis was undertaken of two clinical trials in patients with cancer cachexia (n = 654). Pain, depression, and fatigue were assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30. Plasma C-reactive protein (CRP) was measured as a marker of SI in a subgroup (n = 436). Multivariate analysis and a series of regression analyses were undertaken relating pain, depression, fatigue, and CRP. RESULTS Pain, depression, and fatigue clustered, with between two and four times as many patients having all three symptoms as would be expected if the symptoms only coexist by chance (P < 0.001). CRP was not related to the symptom cluster. There was a strong relationship between the pattern of symptoms and physical functioning (P < 0.001). CONCLUSION Pain, depression, and fatigue is an identifiable symptom cluster in a cohort of cachexic cancer patients and is associated with reduced physical functioning.

Challenges in cancer pain management – bone pain

Whilst not strictly a neuropathic injury, cancer-induced bone pain (CIBP) is a unique state with features of neuropathy and inflammation. Recent work has demonstrated that osteoclasts damage peripheral nerves (peptidergic C fibres and SNS) within trabeculated bone leading to deafferentation. In addition, glia cell activation and neuronal hyperexcitability within the dorsal horn, are all similar to a neuropathy. Gabapentin and carbamazepine (both anti-convulsants that modulate neuropathy) are effective at attenuating dorsal horn neuronal excitability and normalizing pain-like behaviours in a rat model of CIBP. However alterations in neuroreceptors in the dorsal horn do not mimic neuropathy, rather only dynorphin is upregulated, glia cells are active and hypertrophic and c-fos expression is increased post-noxious behavioural stimulus. CIBP perhaps illustrates best the complexity of cancer pains. Rarely are they purely neuropathic, inflammatory, ischaemic or visceral but rather a combination. Management is multimodal with radiotherapy, analgesics (opioids, NSAIDs), bisphosphonates, radioisotopes and tumouricidal therapies. The difficulty with opioids relates to efficacy on spontaneous pain at rest and movement-related pain. Potential adjuvants to standard analgesic therapies for CIBP are being explored in clinical trials and include inhibitors of glutamate release.

Translational medicine: cancer pain mechanisms and management

Cancer-induced bone pain (CIBP) is a major clinical problem with up to 85% of patients with bony metastases having pain, often associated with anxiety and depression, reduced performance status, and a poor quality of life. Malignant bone disease creates a chronic pain state through sensitization and synaptic plasticity within the spinal cord that amplifies nociceptive signals and their transmission to the brain. Fifty per cent of patients are expected to gain adequate analgesia from palliative radiotherapy within 4-6 weeks of treatment. Opioid analgesia does make a useful contribution to the management of CIBP, especially in terms of suppressing tonic background pain. However, CIBP remains a clinical challenge because the spontaneous and movement-related components are more difficult to treat with opioids and commonly used analgesic drugs, without unacceptable side-effects. Recently developed laboratory models of CIBP, which show congruency with the clinical syndrome, are contributing to an improved understanding of the neurobiology of CIBP. This chronic pain syndrome appears to be unique and distinct from other chronic pain states, such as inflammatory or neuropathic pain. This has clear implications for treatment and development of future therapies. A translational medicine approach, using a highly iterative process between the clinic and the laboratory, may allow improved understanding of the underlying mechanisms of CIBP to be rapidly translated into real clinical benefits in terms of improved pain management.

Animal models of bone cancer pain: Systematic review and meta-analyses

&NA; Systematic review identified 38 animal models of bone cancer pain. Reported methodological quality was low; improving this may enhance translation to the clinic. &NA; Pain can significantly decrease the quality of life of patients with advanced cancer. Current treatment strategies often provide inadequate analgesia and unacceptable side effects. Animal models of bone cancer pain are used in the development of novel pharmacological approaches. Here we conducted a systematic review and meta‐analysis of publications describing in vivo modelling of bone cancer pain in which behavioural, general health, macroscopic, histological, biochemical, or electrophysiological outcomes were reported and compared to appropriate controls. In all, 150 publications met our inclusion criteria, describing 38 different models of bone cancer pain. Reported methodological quality was low; only 31% of publications reported blinded assessment of outcome, and 11% reported random allocation to group. No publication reported a sample size calculation. Studies that reported measures to reduce bias reported smaller differences in behavioural outcomes between tumour‐bearing and control animals, and studies that presented a statement regarding a conflict of interest reported larger differences in behavioural outcomes. Larger differences in behavioural outcomes were reported in female animals, when cancer cells were injected into either the tibia or femur, and when MatLyLu prostate or Lewis Lung cancer cells were used. Mechanical‐evoked pain behaviours were most commonly reported; however, the largest difference was observed in spontaneous pain behaviours. In the spinal cord astrocyte activation and increased levels of Substance P receptor internalisation, c‐Fos, dynorphin, tumor necrosis factor‐&agr; and interleukin‐1&bgr; have been reported in bone cancer pain models, suggesting several potential therapeutic targets. However, the translational impact of animal models on clinical pain research could be enhanced by improving methodological quality.

Are cancer pain and depression interdependent? A systematic review.

Objective: Pain and depression are common in cancer patients. As these are both highly prevalent, the issue of a possible interdependent association has been raised. The aim of this systematic review was to examine the available literature and explore whether there is any evidence to support a causal relationship between cancer pain and depression.

NMDA receptor antagonist treatment at the time of nerve injury prevents injury-induced changes in spinal NR1 and NR2B subunit expression and increases the sensitivity of residual pain behaviours to subsequently administered NMDA receptor antagonists

&NA; Spinal NMDA receptors (NMDA R) are important in neuropathic sensitisation and acute administration of antagonists can provide temporary attenuation of sensitisation. If establishment of the chronic pain state could be prevented by brief administration of such agents at or around the time of nerve injury (pre‐emptive analgesia) it might be possible to avoid many of the unacceptable side effects associated with repeated administration of these or other antagonists. Several reports describe aspects of effective pre‐emptive analgesia from NMDA R antagonists in animal models of neuropathic pain. The first aim of the present study was to make a direct comparison of changes in mechanical allodynia, cold allodynia and thermal hyperalgesia following nerve injury, demonstrating their increasing degree of susceptibility to pre‐emptive NMDA R antagonist treatment. Secondly, we used immunoblotting and immunohistochemistry to investigate the effects of nerve injury on NMDA receptor subunit expression, revealing increased expression of NR2B, but not NR2A and reduced NR1 in the superficial dorsal horn. These changes were attenuated following NMDA receptor antagonist pre‐treatment. Thirdly, we investigated the pharmacological properties of residual mechanical allodynia and cold allodynia that remained after pre‐emptive treatment and revealed a greater sensitivity to NMDA R antagonists. These findings indicate that in addition to a marked suppression of thermal hyperalgesia and cold allodynia, pre‐emptive treatment with NMDA R antagonist causes a lasting change in spinal NMDA R complexes such that remaining mechanical allodynia should be more effectively targeted by NMDA R antagonists.

Management of Cancer Pain: Basic Principles and Neuropathic Cancer Pain

Pain is one of the commonest symptoms in patients with cancer occurring in as many as 90% of patients during their illness. Pain is a complex phenomenon, which can be exacerbated by numerous other factors. This paper discusses the common strategies for the management of cancer pain in general and also neuropathic cancer pain. Using the World Health Organisation (WHO) analgesic ladder for cancer pain relief, 80% of cancer pain can usually be controlled. It follows therefore that 20% of cancer pain can be difficult to control. Neuropathic cancer pain is often in this category and the use of adjuvant analgesics such as amitriptyline and gabapentin is important. Optimum cancer pain control is achieved by integrating standard analgesic approaches during tumouricidal therapy or any other active cancer treatment.

Opioid-induced hyperalgesia: a clinical challenge

There is an increasing body of literature from both clinical and basic science studies regarding opioid-induced hyperalgesia (OIH). Although there has been debate about its clinical relevance, it is becoming clear that OIH presents a clinical challenge in acute, chronic, and cancer pain settings. OIH is a paradoxical response to an opioid agonist, whereby instead of an analgesic, or antinociceptive effect occurring, there is an increase in pain perception. This may occur in the area of the pain being treated or may be a more generalized increase in pain, often with features associated with neuropathic pain, such as hyperalgesia or allodynia. It is different from tolerance, where an increased dose of opioid is required to get the same analgesic effect, but there is no increase in pain as a result of opioid administration. In order to address this problem, a greater understanding of the underlying mechanisms and more knowledge about its clinical manifestations of OIH are needed. Basic science studies are beginning to clarify some of the contributory mechanisms, many of which are similar to those that underlie the development of tolerance. From laboratory models of OIH, it is clear that, as with many chronic pain states, there are both peripheral and central changes in nociceptive processing. Alterations in the spinal cord are important, with some form of central sensitization occurring. This is likely to involve the ionotropic glutamate receptor, the N-methyl-D-aspartate (NMDA) receptor, known to play a key role in central sensitization. In rodent models of OIH, using chronic opioid administration, C-fibre potentiation has been demonstrated, similar to that seen with central sensitization. This can be prevented with NMDA receptor block and a range of studies have demonstrated the efficacy of NMDA receptor antagonists in preventing OIH. 3 Spinal neurones in culture show increased NMDA receptor activity after chronic morphine administration, also seen acutely with remifentanil or a dynorphin agonist. Further evidence for the involvement of glutamate comes from work using gabapentin, which has a presynaptic effect on glutamate release, and dose dependently decreases OIH from repeat fentanyl in rats. Minville and colleagues, in this issue of the British Journal of Anaesthesia, present findings that add further weight to the importance of the NMDA receptor in acute OIH. Their model has the benefits of more closely mimicking the clinical situation than some previous models, and as such their findings may be more directly translatable. Using a mouse fracture model combined with intramedullary pinning, and intermittent parenteral administration of sufentanil, they demonstrated the development of both mechanical and thermal hyperalgesia, after an initial antinociceptive effect. This OIH was prevented by ketamine, which also prevented the reduced efficacy of postoperative morphine if sufentanil was given alone. Modulation of spinal input by descending pathways from the brainstem is also implicated in the development of OIH, with a shift in the balance between descending inhibitory control towards pronociceptive systems. These pronociceptive systems may be more active in certain chronic pain states and also seems to play a role in OIH, acting via 5-HT3 and possibly 5-HT2 receptors. Ondansetron, a widely used 5-HT3 antagonist, blocks signs of OIH. Several endogenous neuropeptides may also work via descending spinal pathways, with increased endogenous cholecystokinin (CCK) in the brainstem contributing to OIH, with this effect being reversed by CCK-2 antagonists. Substance P, acting via NK-1 receptors, may also be involved, as destruction of NK-1 containing neurones, with the toxin saporin, prevents OIH. 9 Spinal administration of an NK-1 antagonist reverses OIH, with increased NK-1 receptor internalization in the dorsal horn detected in OIH. The NK-1 receptor may also interact with NMDA receptors to modify descending control.