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Nociceptive and neuropathic pain signals are known to result from noxious stimuli, which are converted into electrical impulses within tissue nociceptors. There is a complex equilibrium of pain-signalling and pain-relieving pathways connecting PNS and CNS. Drugs against long-term pain are today directed against increased neuronal excitability, mostly with less success. An injury often starts with acute physiological pain, which becomes inflammatory, nociceptive, or neuropathic, and may be transferred into long-term pain. Recently a low-grade inflammation was identified in the spinal cord and along the pain pathways to thalamus and the parietal cortex. This neuroinflammation is due to activation of glial cells, especially microglia, with production of cytokines and other inflammatory mediators within the CNS. Additionally, substances released to the blood from the injured region influence the blood–brain barrier, and give rise to an increased permeability of the tight junctions of the capillary endothelial cells, leading to passage of blood cells into the CNS. These cells are transformed into reactive microglia. If the inflammation turns into a pathological state the astrocytes will be activated. They are coupled into networks and respond to substances released by the capillary endothelial cells, to cytokines released from microglia, and to neurotransmitters and peptides released from neurons. As the astrocytes occupy a strategic position between the vasculature and synapses, they monitor the neuronal activity and transmitter release. Increased release of glutamate and ATP leads to disturbances in Ca 2+ signalling, increased production of cytokines and free radicals, attenuation of the astrocyte glutamate transport capacity, and conformational changes in the astrocytic cytoskeleton, the actin filaments, which can lead to formation and rebuilding of new synapses. New neuronal contacts are established for maintaining and spreading pain sensation with the astrocytic networks as bridges. Thereby the glial cells can maintain the pain sensation even after the original injury has healed, and convert the pain into long-term by altering neuronal excitability. It can even be experienced from other parts of the body. As astrocytes are intimate co-players with neurons in the CNS, more knowledge on astrocyte responses to inflammatory activators may give new insight in our understanding of mechanisms of low-grade inflammation underlying long-term pain states and pain spreading. Novel treatment strategies would be to restore glial cell function and thereby attenuate the neuroinflammation.

In this long-term follow-up study of 175 women, we investigated the prevalence of and factors associated with persisting pain and sensory changes four years after augmentation mammoplasty. Previously the women had participated in an acute postoperative pain study, and follow-up investigations at 6 weeks and 1 year after surgery. In the present study, the women were mailed questionnaires about pain, sensory changes, and affection of daily life, quality of life and pain catastrophizing 4 years after surgery. One hundred and sixteen women answered the questionnaire. The fraction of women reporting evoked- and/or spontaneous pain during the last 24 h had declined from 20% at 1 year to 14% at 4 years. Hyperesthesia had declined from 46% at 1 year to 32% at 4 years, while the change in hypoesthesia was small, 47% at 1 year to 51% at 4 years. Methylprednisolone and parecoxib given pre incisionally reduced acute postoperative pain and reduced the prevalence of hyperesthesia after 6 weeks/1 year, but after 4 years we found no significant differences between the test drug groups. Those having concomitant pain and hyperesthesia at 6 weeks and 1 year had high odds for persisting pain at 4 years (OR 7.8, 95% CI 2.1–29.8, P = 0.003; OR 13.2, 95% CI 2.5–71.3, P = 0.003). In patients without pain but with hyperesthesia at 1 year, the hyperesthesia increased the odds for pain at 4 years (OR 2.6 95% CI 1.1–6.1, P = 0.03). Hypoesthesia at 6 weeks or at 1 year did not affect the odds for pain at 4 years. A good general health condition (mental and physical) was associated with reduced odds for pain at 4 years (OR = 0.56, 95% CI 0.35–0.88, P = 0.01). However, using the Short Form health survey, SF-12, the Mental Component Summary Score seemed to affect the odds for chronic pain more than the Physical Component Summary Score. To conclude, the prevalence of pain and hyperesthesia after breast augmentation declined from 1 to 4 years. Nevertheless, the most striking finding in the current trial was that pain coinciding with hyperesthesia at 6 weeks and 1 year resulted in highly increased odds for persistent postoperative pain. Even hyperesthesia alone, without pain, increased the odds for chronic postsurgical pain. Thus, the present study suggests hyperesthesia as an independent risk factor for chronic postsurgical pain.

Introduction Trismus, or limited mouth opening, is a well-known complication of head and neck cancer and its treatment. It may be caused by tumour infiltration into the masticatory muscles or by treatment like surgery and radiotherapy. A limited mouth opening may have a negative effect on nutrition, phonation, dental hygiene and treatment, and quality of life. The severity of this complication depends on the location of the tumour, the type of reconstruction, the total radiation dose, fractionation, and treatment techniques. If there is no intervention, these changes may be progressive and persist for life. There are no specific treatments for trismus. Current strategies emphasize prevention and, in instances of existing trismus, collaboration between health care professionals to establish pain control, prevent the progression of trismus, and restore function. The prevalence of trismus in head and neck cancer patients ranges from 5% to 38%. Despite numerous studies, reliable data on the aetiology of trismus and appropriate treatment for it are scarce. Case report We describe a patient with squamous cell carcinoma of the oropharynx who developed trismus after surgery and radiotherapy. A multidisciplinary treatment strategy including analgesics, regional blocks, hyperbaric oxygenation therapy, external dynamic bite opener and physiotherapy, increased the mouth opening from 5 mm to 22 mm, however, the patient still suffered from xerostomia and had problems with intake of solid food. Material and methods A systematic literature search (starting January 1., 1980, and ending June 1., 2009) was performed to identify evidence-based interventions for the treatment of trismus in head and neck cancer patients. A total of 244 articles were identified from the databases. Of these, eight were excluded because of the absence of an English abstract and 214 were excluded because they were of marginal relevance to the inclusion criteria. The remaining 22 articles were evaluated independently by two experts using the Scottish Inter-collegiate Guidelines Network criteria for quality and evidence. Results There were few studies of good methodological quality on this topic. Two systematic reviews and two RCTs were identified. The other reports involved cohorts, case series, and expert opinions. Discussion Evidence in the form of clinical studies on therapeutic interventions is scarce. Numerous pharmacological treatment modalities have been described, but few are supported by the results of comparative trials involving control groups. Few studies have documented therapeutic effects for longer than a year. Better evidence was found for non-pharmacological methods, especially for physical therapy with passive and active stretching exercises, an important first-line strategy. The interincisal distance criterion for trismus varies between authors from 15 to 40 mm, which renders comparison between studies difficult. The absence of a standardized assessment protocol may also have contributed to variation between studies. An interincisal distance of 35 mm has been proposed as a definition of trismus. Explicit and precise treatment algorithms could not be established based on the available literature. However, a coordinated multidisciplinary approach in order to estimate and understand patient dysfunction is recommended; a systematic treatment plan should result in good symptom control and patient care. Prevention of trismus is more desirable than treatment for trismus.

A high proportion of patients suffering from neuropathic pain do not receive satisfactory pain relief from their current treatment, due to incomplete efficacy and dose-limiting adverse effects. Hence, one strategy to improve treatment outcome is the use of a combination of analgesic drugs. The potential benefits of such approach include improved and prolonged duration of analgesic effect and fewer or milder adverse effects with lower doses of each drug. Gabapentin is recommended as a first-line drug in the treatment of neuropathic pain, and has recently been demonstrated to act on supraspinal structures to stimulate the descending noradrenergic pain inhibitory system. Hypothetically, the analgesic effect of gabapentin may be potentiated if combined with a drug that prolongs the action of noradrenaline. In this study, gabapentin was co-administered with the serotonin and noradrenaline reuptake inhibitor venlafaxine, and subsequently evaluated for its effect on mechanical hypersensitivity in the rat spared nerve injury model of neuropathic pain. In this model, two branches of the sciatic nerve (the tibial and common peroneal nerves) are ligated and cut, leaving the third branch (the sural nerve) intact to innervate the hind paw of the animal. Treatment-induced ataxia was tested in order to exclude biased effect measurements. Finally, the pharmacokinetics of gabapentin was investigated alone and in combination with venlafaxine to elucidate any alterations which may have consequences for the pharmacological effect and safety. The overall effect on nerve injury-induced hypersensitivity of co-administered gabapentin (60 mg/kg s.c.) and venlafaxine (60 mg/kg s.c.), measured as the area under the effect-time curve during the three hour time course of testing, was similar to the highest dose of gabapentin (200 mg/kg s.c.) tested in the study. However, this dose of gabapentin was associated with ataxia and severe somnolence, while the combination was not. Furthermore, when administered alone, an effect delay of approximately one hour was observed for gabapentin (60 mg/kg s.c.) with maximum effect occurring 1.5 to 2.5 h after dosing, while venlafaxine (60 mg/kg s.c.) was characterised by a rapid onset of action (within 30 min) which declined to baseline levels before the end of the three hour time of testing. The effect of co-administered drugs (both 60 mg/kg s.c.), in the doses used here, can be interpreted as additive with prolonged duration in comparison to each drug administered alone. An isobolographic study design, enable to accurately classify the combination effect into additive, antagonistic or synergistic, was not applied. The pharmacokinetics of gabapentin was not altered by co-administered venlafaxine, implying that a pharmacokinetic interaction does not occur. The effect of gabapentin on the pharmacokinetics of venlafaxine was not studied, since any alterations are unlikely to occur on the basis of the pharmacokinetic properties of gabapentin. In conclusion, the results from this preclinical study support the rationale for improved effect and less adverse effects through combination therapy with gabapentin and venlafaxine in the management of neuropathic pain.

Background and objective Perioperative low-dose ketamine has been useful for postoperative analgesia. In this study we wanted to assess the analgesic effect and possible side-effects of perioperative low-dose S (+) ketamine when added to a regime of non-opioid multimodal pain prophylaxis. Methods Seventy-seven patients scheduled for haemorrhoidectomy were enrolled in this randomized, double-blind, controlled study. They received oral paracetamol 1–2 g, total intravenous anaesthesia, intravenous 8 mg dexamethasone, 30 mg ketorolac and local infiltration with bupivacaine/epinephrine. Patients randomized to S (+) ketamine received an intravenous bolus dose of 0.35 mg kg −1 S (+) ketamine before start of surgery followed by continuous infusion of 5 μg kg −1 min −1 until 2 min after end of surgery. Patients in the placebo group got isotonic saline (bolus and infusion). BISTM monitoring was used. Pain intensity and side-effects were assessed by blinded nursing staff during PACU stay and by phone 1, 7 and 90 days after surgery. Results In patients randomized to S (+) ketamine emergence from anaesthesia was significantly longer (13.1 min vs. 9.3 min; p < 0.001). BIS values were significantly higher during anaesthesia (maximal value during surgery: 62 vs. 57; p = 0.01) and when opening eyes (81 vs. 70, p < 0.001). Pain scores (NRS and VAS) did not differ significantly between groups. Conclusions The addition of perioperative S (+) ketamine for postoperative analgesia after haemorrhoidectomy on top of multimodal non-opioid pain prophylaxis does not seem to be warranted, due to delayed emergence and recovery, more side-effects, altered BIS readings and absence of additive analgesic effect.

Objectives The aim of this study was to explore how the handling of nerves affects the risk for developing sensory disturbances (SDs) following groin hernia surgery. Patients and methods All patients 18 years or older undergoing surgery for inguinal hernia at Mora Hospital, Sweden, during an eight-month period in 2006, were eligible for inclusion. The surgical procedure was recorded prospectively according to a standardised protocol. One year postoperatively all patients were requested to answer the Inguinal Pain Questionnaire as well as a set of 18 sensory and affective pain descriptors. They were also invited to clinical examination including sensory testing. Results Of the 157 hernia repairs in Mora during the period of study, 128 repairs in 116 patients, were registered prospectively according to the study protocol. Laparoscopic total extraperitoneal (TEP) repair was performed in 36 (28%) of the patients. Ninety-two (79%) patients, including five patients operated bilaterally, underwent postoperative examination. SDs were found in 33 (34%) of the groins examined. No descriptor was found that significantly predicted the presence of altered examination findings. No significant association between the intraoperative handling of nerves and SD was seen. In the TEP-group, no SDs were seen. Infiltration of local anaesthetic agents and blockade of the ilioinguinal nerve prior to surgery were found to be significantly associated with SD more than 2 cm away from the scar (both p < 0.05). The presence of SD was not associated with significant pain. Conclusions SDs are common after open hernia surgery, but are not associated with persistent postoperative pain.