Yoram Shir

A novel behavioral model of neuropathic pain disorders produced in rats by partial sciatic nerve injury

&NA; Partial nerve injury is the main cause of causalgiform pain disorders in humans. We present here a novel animal model of this condition. In rats we unilaterally ligated about half of the sciatic nerve high in the thigh. Within a few hours after the operation, and for several months thereafter, the rats developed guarding behavior of the ipsilateral hind paw and licked it often, suggesting the possibility of spontaneous pain. The plantar surface of the foot was evenly hyperesthetic to non‐noxious and noxious stimuli. None of the rats autotomized. There was a sharp decrease in the withdrawal thresholds bilaterally in response to repetitive Von Frey hair stimulation at the plantar side. After a series of such stimuli in the operated side, light touch elicited aversive responses, suggesting allodynia to touch. The withdrawal thresholds to CO2 laser heat pulses were markedly lowered bilaterally. Suprathreshold noxious heat pulses elicited exaggerated responses unilaterally, suggesting thermal hyperalgesia. Pin‐prick evoked such exaggerated responses bilaterally (mechanical hyperalgesia). In a companion report, we show that these abnormalities critically depend on the sympathetic outflow. Based on the immediate onset and long‐lasting perpetuation of similar symptoms, such as touch‐evoked allodynia and hyperalgesia, and the resemblance of the contralateral phenomena to ‘mirror image’ pains in some humans with causalgia, we suggest that this preparation may serve as a model for syndromes of the causalgiform variety that are triggered by partial nerve injury and maintained by sympathetic activity.

Effects of sympathectomy in a model of causalgiform pain produced by partial sciatic nerve injury in rats

&NA; In a previous report we presented a novel behavioral model of neuropathic pain disorders, produced in rat by a unilateral ligation of about half of the sciatic nerve. The model is characterized by rapid onset of behaviors suggesting spontaneous pain and disordered responses to non‐noxious and noxious stimuli. These include reduced withdrawal thresholds to repetitive touch in the partially deafferented skin (“touched‐evoked hyperesthesia”), touch‐evoked allodynia, reduced withdrawal thresholds to noxious thermal stimuli and exaggerated responses to noxious heat and mechanical stimuli (‘thermal hyperalgesia’). Some of these disorders are seen at mirror image sites on the hind limb opposite the lesion. These disorders start within hours after partial nerve injury, last many months and are very similar to causalgia in humans following partial nerve injury. Since sympathetic efferent activity is known to aggravate causalgia in humans and sympathectomy is known to relieve it, we studied the effect of changing sympathetic outflow in the rat model. Reversible sympathectomy was carried out using guanethidine injected intraperitoneally in 3 experiments, each at a different time in relation to the partial nerve injury. We found that: (1) sympathectomy performed several months postoperatively alleviated the sensory disorders bilaterally; (2) sympathectomy prior to nerve injury partially prevented the appearance of thermal hyperalgesia but did not affect hyperesthesia to repetitive touch; and (3) sympathectomy at the time of nerve injury aggravated the sensory disorders during the first few days. As maintenance and production of the sensory disorders in this animal model depended on sympathetic nervous outflow, we conclude that the rats were suffering from a syndrome analogous to sympathetically maintained causalgia in man.

2012 Canadian Guidelines for the diagnosis and management of fibromyalgia syndrome: executive summary.

BACKGROUND Recent neurophysiological evidence attests to the validity of fibromyalgia (FM), a chronic pain condition that affects >2% of the population. OBJECTIVES To present the evidence-based guidelines for the diagnosis, management and patient trajectory of individuals with FM. METHODS A needs assessment following consultation with diverse health care professionals identified questions pertinent to various aspects of FM. A literature search identified the evidence available to address these questions; evidence was graded according to the standards of the Oxford Centre for Evidence-Based Medicine. Drafted recommendations were appraised by an advisory panel to reflect meaningful clinical practice. RESULTS The present recommendations incorporate the new clinical concepts of FM as a clinical construct without any defining physical abnormality or biological marker, characterized by fluctuating, diffuse body pain and the frequent symptoms of sleep disturbance, fatigue, mood and cognitive changes. In the absence of a defining cause or cure, treatment objectives should be patient-tailored and symptom-based, aimed at reducing global complaints and enhancing function. Healthy lifestyle practices with active patient participation in health care forms the cornerstone of care. Multimodal management may include nonpharmacological and pharmacological strategies, although it must be acknowledged that pharmacological treatments provide only modest benefit. Maintenance of function and retention in the workforce is encouraged. CONCLUSIONS The new Canadian guidelines for the treatment of FM should provide health professionals with confidence in the complete care of these patients and improve clinical outcomes.

The Effects of Nabilone on Sleep in Fibromyalgia: Results of a Randomized Controlled Trial

BACKGROUND: Sleep disorders affect many patients with chronic pain conditions. Cannabis has been reported by several patient populations to help sleep. We evaluated the safety and efficacy of nabilone, a synthetic cannabinoid, on sleep disturbance in fibromyalgia (FM), a disease characterized by widespread chronic pain and insomnia. METHODS: We conducted a randomized, double-blind, active-control, equivalency crossover trial to compare nabilone (0.5–1.0 mg before bedtime) to amitriptyline (10–20 mg before bedtime) in patients with FM with chronic insomnia. Subjects received each drug for 2 wk with a 2-wk washout period. The primary outcome was sleep quality, measured by the Insomnia Severity Index and the Leeds Sleep Evaluation Questionnaire. Secondary outcomes included pain, mood, quality of life, and adverse events (AEs). RESULTS: Thirty-one subjects were enrolled and 29 completed the trial (26 women, mean age 49.5 yr). Although sleep was improved by both amitriptyline and nabilone, nabilone was superior to amitriptyline (Insomnia Severity Index difference = 3.2; 95% confidence interval = 1.2–5.3). Nabilone was marginally better on the restfulness (Leeds Sleep Evaluation Questionnaire difference = 0.5 [0.0–1.0]) but not on wakefulness (difference = 0.3 [−0.2 to 0.8]). No effects on pain, mood, or quality of life were observed. AEs were mostly mild to moderate and were more frequent with nabilone. The most common AEs for nabilone were dizziness, nausea, and dry mouth. CONCLUSIONS: Nabilone is effective in improving sleep in patients with FM and is well tolerated. Low-dose nabilone given once daily at bedtime may be considered as an alternative to amitriptyline. Longer trials are needed to determine the duration of effect and to characterize long-term safety.

Correlation of intact sensibility and neuropathic pain-related behaviors in eight inbred and outbred rat strains and selection lines

&NA; In some rat strains, total hindpaw denervation triggers autotomy, a behavior of self mutilation presumably related to neuropathic pain. Partial sciatic ligation (PSL) in rats produces tactile allodynia and heat hyperalgesia but not autotomy. Our aims in this study were to examine: (1) whether sensibility of intact rats to noxious and non‐noxious stimuli is strain‐dependent; (2) whether sensibility of intact rats could predict levels of autotomy, or of allodynia and hyperalgesia in the PSL model; and (3) whether autotomy levels are correlated with levels of allodynia or hyperalgesia. Here we report that in two inbred rat strains (Lewis and Fisher 344), two outbred rat strains (Sabra and Sprague–Dawley) and four selection lines of rats (Genetically Epilepsy‐Prone Rats, High Autotomy, Low Autotomy and Flinders Sensitive Line), tactile sensitivity and response duration to noxious heat of intact animals were strain‐dependent. Levels of autotomy following hindpaw denervation and of allodynia and hyperalgesia in the PSL model were also strain‐dependent. Thus, these traits are determined in part by genetic factors. Sensory sensibility of intact rats was not correlated with levels of autotomy following total denervation, or allodynia and hyperalgesia following partial denervation. We suggest that preoperative sensibility of intact rats is not a predictor of levels of neuropathic disorders following nerve injury. Likewise, no correlation was found between autotomy, allodynia and hyperalgesia, suggesting that neuropathic pain behaviors triggered by nerve injury of different etiologies are mediated by differing mechanisms.

Treatment of Fibromyalgia Syndrome: Recommendations of Recent Evidence-Based Interdisciplinary Guidelines with Special Emphasis on Complementary and Alternative Therapies

Objective. Current evidence indicates that there is no single ideal treatment for fibromyalgia syndrome (FMS). First choice treatment options remain debatable, especially concerning the importance of complementary and alternative medicine (CAM) treatments. Methods. Three evidence-based interdisciplinary guidelines on FMS in Canada, Germany, and Israel were compared for their first choice and CAM-recommendations. Results. All three guidelines emphasized a patient-tailored approach according to the key symptoms. Aerobic exercise, cognitive behavioral therapy, and multicomponent therapy were first choice treatments. The guidelines differed in the grade of recommendation for drug treatment. Anticonvulsants (gabapentin, pregabalin) and serotonin noradrenaline reuptake inhibitors (duloxetine, milnacipran) were strongly recommended by the Canadian and the Israeli guidelines. These drugs received only a weak recommendation by the German guideline. In consideration of CAM-treatments, acupuncture, hypnosis/guided imagery, and Tai Chi were recommended by the German and Israeli guidelines. The Canadian guidelines did not recommend any CAM therapy. Discussion. Recent evidence-based interdisciplinary guidelines concur on the importance of treatment tailored to the individual patient and further emphasize the need of self-management strategies (exercise, and psychological techniques).

Neuropathic pain following partial nerve injury in rats is suppressed by dietary soy

Some humans with partial nerve injury present a syndrome of neuropathic sensory disorders which depend on the sympathetic activity (sympathetically-maintained pain, SMP). Several years ago we introduced a rat model for SMP, produced by tightly ligating 1/3-1/2 of the sciatic nerve, leading to a partial denervation of the hindpaw (Partial Sciatic Ligation, PSL model) [Seltzer, Z., Dubner, R. and Shir, Y., Pain, 43 (1990) 245-250]. After working with this model for several years we encountered difficulties in replicating it although rat strain, vendor, gender, age and weight, surgical approach and sensory testing procedures were not changed. We report here that this variability can be attributed, at least in part, to the diet the animals consumed. Rats fed perioperatively with soy-containing diets expressed significantly weaker neuropathic sensory disorders compared to rats fed on soy-free diets. We conclude that diet may greatly affect experimental outcome in the PSL model.

Management of Chronic Arthritis Pain in the Elderly

Musculoskeletal pain in the elderly is common and disabling. As the conditions causing rheumatic pain, including osteoarthritis, inflammatory arthritis and soft-tissue conditions such as tendonitis and bursitis, are, for the most part, not curable, pain control is paramount in order to maintain quality of life. Pain management should be multimodal and tailored to the individual patient, and will likely include a combination of both nonpharmacological and pharmacological interventions.Nonpharmacological treatments begin with education of the patient, encouragement to practise self-management strategies and attention to healthy life habits such as weight control and regular physical activity and exercise. Advice in this regard may be effectively given by healthcare professionals other than physicians. Although herbal products and nutritional supplements are commonly used by patients, studies of their efficacy and safety, especially in the elderly, are limited. In contrast, topical applications, and in particular those containing NSAIDs, are being used more frequently, are associated with fewer adverse effects than oral preparations and offer a new and safer treatment alternative. Similarly, intra-articular and soft-tissue injections of corticosteroids provide an easy and cost-effective option for symptom relief with minimal risk.The use of any pharmacological agent in the elderly should be tempered with caution regarding increased sensitivity to medications, drug-drug interactions and associated co-morbidities. Therefore, the elderly will often require down-adjustment of dosage and careful attention to the risk/benefit ratio of the treatment. There is, however, no single ideal pain medication for management of rheumatic pain. The four broad categories of treatments, namely simple analgesics (i.e. paracetamol [acetaminophen]), NSAIDs, stronger analgesics (i.e. opioids) and adjuvant drugs, each have unique and particular concerns regarding their adverse effect profiles. The continued use of any medication should also be repeatedly assessed to ensure that efficacy is maintained. Throughout the treatment period, physicians must remain vigilant for emergent adverse effects.Patients and physicians should have realistic outcome goals for effective rheumatic pain management. Although complete pain relief is seldom achieved, modulation of pain and the associated components of sleep disturbance, fatigue and mood disorder will improve overall quality of life in the elderly. However, barriers to effective pain management from both the patient and the healthcare professional perspectives still exist, and will be overcome only by educational efforts.Successful rheumatic pain management in the elderly should begin with an accurate diagnosis by the physician, and patients must be realistic in their expectations. Treatments should be multimodal, with attention given to the co-morbidities of pain as well as the global health status of the patient. Whether or not an outcome is favourable should be determined not only by the treatment’s impact on pain but also by its capacity to improve function and enhance quality of life. The wider range of treatment options now available is both useful and encouraging for the physician managing musculoskeletal aches and pain in the elderly.

Opioid Use, Misuse, and Abuse in Patients Labeled as Fibromyalgia

BACKGROUND As pain is the cardinal symptom of fibromyalgia, it is logical that treatments directed toward pain relief will be commonly used. Analgesic drug therapy remains the traditional treatment intervention for most chronic pain conditions, with a progressive increased use of opioids in the past 20 years. Concerns about efficacy, risk-benefit ratio, and possible long-term effects of chronic opioid therapy have been raised. There is limited information about opioid treatment in fibromyalgia, with all current guidelines discouraging opioid use. METHODS A chart review of all patients referred to a tertiary care pain center clinic with a referring diagnosis of fibromyalgia was conducted to evaluate use of opioid medications. RESULTS We have recorded opioid use by 32% of 457 patients referred to a multidisciplinary fibromyalgia clinic, with over two thirds using strong opioids. Opioid use was more commonly associated with lower education, unemployment, disability payments, current unstable psychiatric disorder, a history of substance abuse, and previous suicide attempts. CONCLUSION We have observed negative health and psychosocial status in patients using opioids and labeled as fibromyalgia. Prolonged use of opioids in fibromyalgia requires evaluation.

Soy-containing diet suppresses chronic neuropathic sensory disorders in rats.

Partial sciatic nerve ligation (PSL) in rodents produces chronic neuropathic sensory disorders resembling neuropathic pain in humans. We previously reported that levels of allodynia and hyperalgesia after PSL injury were markedly attenuated by consumption of soy-containing diets. Here we aimed to show that dietary effect on pain behavior is not specific to a certain laboratory. For this purpose, experiments were conducted in a different laboratory (Baltimore rather than Jerusalem) and a different rat strain (Wistar rather than Sabra), with additional and different testing methods (radiant heat from a lamp rather than a CO2 laser). Rats were fed two soy-free diets and a soy-containing one for 28 days. The sensitivity of rats to nonnoxious and noxious stimuli was determined before PSL injury, and levels of neuropathic sensory disorders were determined after it. We found that consuming the soy-containing diet prevented development of tactile and heat allodynia, but not mechanical hyperalgesia. This dietary effect was not correlated with calorie intake and weight gain or dietary concentration of fat and carbohydrates. We conclude that, regardless of experimental site, diet markedly affects chronic neuropathic sensory disorders in rats and should be standardized in animal models of pain.