[Interdisciplinary position paper: the value of radiofrequency denervation in the treatment of chronic pain]. / Interdisziplinäres Positionspapier: der Stellenwert der Radiofrequenzdenervierung in der Therapie chronischer Schmerzen.

Radiofrequency denervation has been established for many years as an important minimally invasive procedure for the treatment of chronic pain conditions. Positive experiences of many users for various indications are contrasted by a nonuniform evidence. With meticulous patient selection and correct assessment of the indications a longer term reduction of pain, a reduced need for analgesics and an improvement in the quality of life can be achieved. The aim of this interdisciplinary position paper is to present the value of radiofrequency denervation in the treatment of chronic pain. The summarized recommendations of the expert group are based on the available evidence and on the clinical experiences of Austrian centers that frequently implement the procedure. The position paper contains recommendations on patient selection and proven indications. We discribe safety aspects, complications, side effects and contraindications.

TRPV1 antagonist BCTC inhibits pH 6.0-induced pain in human skin.

Tissue acidosis due to ischemia occurs under several pathological conditions and is believed to contribute to pain in these circumstances. TRPV1, TRPA1, and ASICs are known to be sensitive to acidic pH. Addressing their possible role in acidosis perception, the respective antagonists BCTC, A-967079, and amiloride were injected in the volar forearm skin of 32 healthy volunteers. To investigate possible redundancies between channels, a full-factorial study design was used. Injections were performed in a prerandomized, double-blind, and balanced design. Each injection included a three-step pH protocol from pH 7.0 over pH 6.5 to pH 6.0 with a step duration of 90 seconds. Pain was reported by volunteers on a numerical scale every 10 seconds during injections. Confirming the primary hypothesis, the combination of all 3 antagonists reduced acid-induced pain at pH 6.0. Because of the full-factorial design, it could be concluded that BCTC alone, but not A-967079 or amiloride, or any combination thereof, was responsible for the observed effects, suggesting TRPV1 as primary sensor for pH 6.0-induced pain. Surprisingly, A-967079 even enhanced pain induced by pH 6.0. In cultured mouse dorsal root ganglion neurons, TPRV1 dependence of pH 6-induced calcium responses could be confirmed. Responses of hTRPV1 to acidic stimulation showed a maximum around pH6, providing an explanation for the pH-dependent inhibition by BCTC. A-967079 sensitizes pH responses is a TRPA1-responsive dorsal root ganglion neuron population, and a direct effect of A-967079 on hTRPA1 and hTRPV1 was excluded. In conclusion, inhibiting TRPV1-mediated acidosis-induced pain could be a symptomatic and potentially also a disease-modifying approach.

A Human TRPA1-Specific Pain Model.

The cation channel transient receptor potential ankyrin 1 (TRPA1) plays an important role in sensing potentially hazardous substances. However, TRPA1 species differences are substantial and limit translational research. TRPA1 agonists tested previously in humans also have other targets. Therefore, the sensation generated by isolated TRPA1 activation in humans is unknown. The availability of 2-chloro-N-(4-(4-methoxyphenyl)thiazol-2-yl)-N-(3-methoxypropyl)-acetamide (JT010), a potent and specific TRPA1 agonist, allowed us to explore this issue. To corroborate the specificity of JT010, it was investigated whether the TRPA1 antagonist (1E,3E)-1-(4-fluorophenyl)-2-methyl-1-penten-3-one oxime (A-967079) abolishes JT010-elicited pain. Sixteen healthy volunteers of both sexes rated pain due to intraepidermal injections of different concentrations and combinations of the substances. The study design was a double-blind crossover study. All subjects received all types of injections, including a placebo without substances. Injections of the TRPA1 agonist dose-dependently caused pain with a half-maximal effective concentration of 0.31 µm Coinjection of A-967079 dose-dependently reduced and at a high concentration abolished JT010-induced pain. Quantification of JT010 by HPLC showed that a substantial part is adsorbed when in contact with polypropylene surfaces, but that this was overcome by handling in glass vials and injection using glass syringes. Isolated TRPA1 activation in humans causes pain. Thus, intradermal JT010 injection can serve as a tool to validate new TRPA1 antagonists concerning target engagement. More importantly, TRPA1-specific tools allow quantification of the TRPA1-dependent component in physiology and pathophysiology.SIGNIFICANCE STATEMENT This study showed that activation of the ion channel transient receptor potential ankyrin 1 (TRPA1) alone indeed suffices to elicit pain in humans, independent of other receptors previously found to be involved in pain generation. The newly established TRPA1-specific pain model allows different applications. First, it can be tested whether diseases are associated with compromised or exaggerated TRPA1-dependent painful sensations in the skin. Second, it can be investigated whether a new, possibly systemically applied drug directed against TRPA1 engages its target in humans. Further, the general possibility of quantitative inhibition of TRPA1 allows identification of the TRPA1-dependent disease component, given that the substance reaches its target. This contributes to a better understanding of pathophysiology, can lay the basis for new therapeutic approaches, and can bridge the gap between preclinical research and clinical trials.

European Pain Federation (EFIC) position paper on appropriate use of cannabis-based medicines and medical cannabis for chronic pain management.

Cannabis-based medicines are being approved for pain management in an increasing number of European countries. There are uncertainties and controversies on the role and appropriate use of cannabis-based medicines for the management of chronic pain. EFIC convened a European group of experts, drawn from a diverse range of basic science and relevant clinical disciplines, to prepare a position paper to empower and inform specialist and nonspecialist prescribers on appropriate use of cannabis-based medicines for chronic pain. The expert panel reviewed the available literature and harnessed the clinical experience to produce these series of recommendations. Therapy with cannabis-based medicines should only be considered by experienced clinicians as part of a multidisciplinary treatment and preferably as adjunctive medication if guideline-recommended first- and second-line therapies have not provided sufficient efficacy or tolerability. The quantity and quality of evidence are such that cannabis-based medicines may be reasonably considered for chronic neuropathic pain. For all other chronic pain conditions (cancer, non-neuropathic noncancer pain), the use of cannabis-based medicines should be regarded as an individual therapeutic trial. Realistic goals of therapy have to be defined. All patients must be kept under close clinical surveillance. As with any other medical therapy, if the treatment fails to reach the predefined goals and/or the patient is additionally burdened by an unacceptable level of adverse effects and/or there are signs of abuse and misuse of the drug by the patient, therapy with cannabis-based medicines should be terminated. SIGNIFICANCE: This position paper provides expert recommendations for nonspecialist and specialist healthcare professionals in Europe, on the importance and the appropriate use of cannabis-based medicines as part of a multidisciplinary approach to pain management, in properly selected and supervised patients.

The therapeutic nuclear magnetic resonance changes the balance in intracellular calcium and reduces the interleukin-1ß induced increase of NF-κB activity in chondrocytes.

OBJECTIVES: Osteoarthritis as the main chronic joint disease is characterised by the destruction of articular cartilage. Developing new, more effective and in particular non-invasive methods to achieve pain reduction of OA patients are of exceptional interest. Clinical observations demonstrated positive effects of therapeutically applied low nuclear magnetic resonance (NMRT) for the treatment of painful disorders of the musculoskeletal system. In this study the cellular mechanism of action of NMRT was examined on chondrocytes. METHODS: Cal-78 human chondrosarcoma cells were kept under inflammatory conditions by application of IL-1ß. NMRT treated cells were tested for changes in histamine induced Ca2+ release by fura-2 calcium imaging. The effects of IL-1ß and of NMRT treatment were further tested by determining intracellular ATP concentrations and the activity of MAP-kinases and NF-κB. RESULTS: NMRT influenced the intracellular calcium signalling by elevating the basal [Ca2+]i. The peak calcium concentration evoked by 10 µM histamine was increased by IL-1ß and this increase was reversed under NMRT treatment. Screening of different kinase-activities revealed an apparent increase in activity of MAPK/ERK and MAPK/JNK in NMRT stimulated cells, p38 was downregulated. The IL-1ß-induced decline in intracellular ATP and the elevated NF-κB activity was reversed under NMRT stimulation. CONCLUSIONS: Under inflammatory conditions, NMRT influenced cellular functions by modulating cellular calcium influx and/or calcium release. Further, NMRT induced changes in MAPK activities such as down-regulation of NF-κB and increasing intracellular ATP might help to stabilise chondrocytes and delay cartilage damage due to OA.

Treatment for chronic low back pain: the focus should change to multimodal management that reflects the underlying pain mechanisms.

Chronic low back pain: Chronic pain is the most common cause for people to utilize healthcare resources and has a considerable impact upon patients' lives. The most prevalent chronic pain condition is chronic low back pain (CLBP). CLBP may be nociceptive or neuropathic, or may incorporate both components. The presence of a neuropathic component is associated with more intense pain of longer duration, and a higher prevalence of co-morbidities. However, many physicians' knowledge of chronic pain mechanisms is currently limited and there are no universally accepted treatment guidelines, so the condition is not particularly well managed. DIAGNOSIS: Diagnosis should begin with a focused medical history and physical examination, to exclude serious spinal pathology that may require evaluation by an appropriate specialist. Most patients have non-specific CLBP, which cannot be attributed to a particular cause. It is important to try and establish whether a neuropathic component is present, by combining the findings of physical and neurological examinations with the patient's history. This may prove difficult, however, even when using screening instruments. Multimodal management: The multifactorial nature of CLBP indicates that the most logical treatment approach is multimodal: i.e. integrated multidisciplinary therapy with co-ordinated somatic and psychotherapeutic elements. As both nociceptive and neuropathic components may be present, combining analgesic agents with different mechanisms of action is a rational treatment modality. Individually tailored combination therapy can improve analgesia whilst reducing the doses of constituent agents, thereby lessening the incidence of side effects. CONCLUSIONS: This paper outlines the development of CLBP and the underlying mechanisms involved, as well as providing information on diagnosis and the use of a wide range of pharmaceutical agents in managing the condition (including NSAIDs, COX-2 inhibitors, tricyclic antidepressants, opioids and anticonvulsants), supplemented by appropriate non-pharmacological measures such as exercise programs, manual therapies, behavioral therapies, interventional pain management and traction. Surgery may be appropriate in carefully selected patients.

Clinical update on benefit versus risks of oral paracetamol alone or with codeine: still a good option?

BACKGROUND: After decades of worldwide use of paracetamol/acetaminophen as a popular and apparently safe prescription and over-the-counter medicine, the future role of this poorly understood analgesic has been seriously questioned by recent concerns about prenatal, cardiovascular (CV) and hepatic safety, and also about its analgesic efficacy. At the same time the usefulness of codeine in combination products has come under debate. METHODS: Based on a PubMed database literature search on the terms efficacy, safety, paracetamol, acetaminophen, codeine and their combinations up to and including June 2016, this clinical update reviews the current evidence of the benefit and risks of oral paracetamol alone and with codeine for mild-to-moderate pain in adults, and compares the respective efficacy and safety profiles with those of nonsteroidal anti-inflammatory drugs (NSAIDs). RESULTS: Whereas there is a clear strong association of NSAID use and gastrointestinal (GI) and CV morbidity and mortality, evidence for paracetamol with and without codeine supports the recommended use even in most vulnerable individuals, such as the elderly, pregnant women, alcoholics, and compromised GI and CV patients. The controversies and widespread misconceptions about the complex hepatic metabolism and potential hepatotoxicity have been corrected by recent reviews, and paracetamol remains the first-line nonopioid analgesic in patients with liver diseases if notes of caution are applied. CONCLUSION: Due to its safety and tolerability profile paracetamol remained a first-line treatment in many international guidelines. Alone and with codeine it is a safe and effective option in adults, whilst NSAIDs are obviously less safe as alternatives, given the risk of potentially fatal GI and CV adverse effects.

MTHFR and ACE Polymorphisms Do Not Increase Susceptibility to Migraine Neither Alone Nor in Combination.

OBJECTIVE: The aim of this study was to confirm previous reports in order to substantiate the hypothesis that functional variants of two genes, namely methylenetetrahydrofolate reductase and angiotensin I converting enzyme, both involved in an important pathway of migraine, increase migraine susceptibility when present in combination. BACKGROUND: Migraine is a complex genetic disease. The migraine attack is thought to be the result of an interaction of neuronal and vascular events, possibly originating in the brainstem leading to activation of the pain processing trigeminovascular system. Functional variants in the methylenetetrahydrofolate gene and the angiotensin I converting enzyme have influence on vascular mechanism and have been investigated intensively in migraine. The published results were inconsistent; however, both polymorphisms in combination have been shown to increase migraine susceptibility. METHODS: In this genetic association study, the prevalence of the functionally relevant polymorphisms C677T in the MTHFR gene and I/D polymorphism in the ACE gene was compared in 420 patients with migraine vs 258 migraine-free controls using a chi-square statistic and binary logistic regression. RESULTS: Susceptibility to any type of migraine (migraine with aura, migraine without aura, and both types combined) was neither increased by each polymorphism on its own, nor in combination (MTHFR: X(2) = 0.18 [P = .91]; ACE: X(2) = 1.62 [P = .45]; combined: OR = 1.02 [95% CI 0.98-1.05] P = .97). CONCLUSIONS: We could not replicate a previous study that showed significant increase in migraine susceptibility for two functional polymorphisms in genes affecting relevant pathways.

Efficacy of Duloxetine in Chronic Low Back Pain with a Neuropathic Component: A Randomized, Double-blind, Placebo-controlled Crossover Trial.

BACKGROUND: Among patients with chronic low back pain (CLBP), approximately 37% show signs of a neuropathic pain component (radicular pain). Treatment of this condition remains challenging. Therefore, the current study aimed to investigate the efficacy of duloxetine in the treatment of CLBP patients with neuropathic leg pain. METHODS: The study was conducted as a prospective, randomized, placebo-controlled, double-blind crossover trial. CLBP with a visual analog scale (VAS) score greater than 5 and a neuropathic component that was assessed clinically and by the painDETECT questionnaire (score > 12) were required for inclusion. Patients were randomly assigned to either duloxetine or placebo for 4 weeks followed by a 2-week washout period before they crossed over to the alternate phase that lasted another 4 weeks. Duloxetine was titrated up to 120 mg/day. The primary outcome parameter was mean VAS score during the last week of treatment in each phase (VAS(week4)). RESULTS: Of 41 patients, 21 patients completed both treatment phases. In the intention-to-treat analysis (n = 25), VAS(week4) was significantly lower in the duloxetine phase compared with placebo (4.1 ± 2.9 vs. 6.0 ± 2.7; P = 0.001), corresponding to an average pain reduction of 32%. The painDETECT score at the end of each treatment phase was significantly lower in the duloxetine phase compared with placebo (17.7 ± 5.7 vs. 21.3 ± 3.6 points; P = 0.0023). Adverse events were distributed equally between the duloxetine (65%) and placebo phases (62%) (P = 0.5). CONCLUSION: In this crossover study, duloxetine proved to be superior to placebo for the treatment of CLBP with a neuropathic leg pain.

A holistic approach to chronic pain management that involves all stakeholders: change is needed.

Chronic pain affects a large proportion of the population, imposing significant individual distress and a considerable burden on society, yet treatment is not always instituted and/or adequate. Comprehensive multidisciplinary management based on the biopsychosocial model of pain has been shown to be clinically effective and cost-efficient, but is not widely available. A literature review of stakeholder groups revealed many reasons for this, including: i) many patients believe healthcare professionals lack relevant knowledge, and consultations are rushed, ii) general practitioners consider that pain management has a low priority and is under-resourced, iii) pain specialists cite non-adherence to evidence-based treatment, sub-optimal prescribing, and chronic pain not being regarded as a disease in its own right, iv) nurses', pharmacists' and physiotherapists' skills are not fully utilized, and v) psychological therapy is employed infrequently and often too late. Many of the issues relating to physicians could be addressed by improving medical training, both at undergraduate and postgraduate levels - for example, by making pain medicine a compulsory core subject of the undergraduate medical curriculum. This would improve physician/patient communication, increase the use of standardized pain assessment tools, and allow more patients to participate in treatment decisions. Patient care would also benefit from improved training for other multidisciplinary team members; for example, nurses could provide counseling and follow-up support, psychologists offer coping skills training, and physiotherapists have a greater role in rehabilitation. Equally important measures include the widespread adoption of a patient-centered approach, chronic pain being recognized as a disease in its own right, and the development of universal guidelines for managing chronic non-cancer pain. Perhaps the greatest barrier to improvement is lack of political will at both national and international level. Some powerful initiatives and collaborations are currently lobbying policy-making bodies to raise standards and reduce unnecessary pain - it is vital they continue.

Pain in the cancer patient: different pain characteristics CHANGE pharmacological treatment requirements.

Twenty years ago, the main barriers to successful cancer pain management were poor assessment by physicians, and patients' reluctance to report pain and take opioids. Those barriers are almost exactly the same today. Cancer pain remains under-treated; in Europe, almost three-quarters of cancer patients experience pain, and almost a quarter of those with moderate to severe pain do not receive any analgesic medication. Yet it has been suggested that pain management could be improved simply by ensuring that every consultation includes the patient's rating of pain, that the physician pays attention to this rating, and a plan is agreed to increase analgesia when it is inadequate. After outlining current concepts of carcinogenesis in some detail, this paper describes different methods of classifying and diagnosing cancer pain and the extent of current under-treatment. Key points are made regarding cancer pain management. Firstly, the pain may be caused by multiple different mechanisms and therapy should reflect those underlying mechanisms - rather than being simply based on pain intensity as recommended by the WHO three-step ladder. Secondly, a multidisciplinary approach is required which combines both pharmacological and non-pharmacological treatment, such as psychotherapy, exercise therapy and electrostimulation. The choice of analgesic agent and its route of administration are considered, along with various interventional procedures and the requirements of palliative care. Special attention is paid to the treatment of breakthrough pain (particularly with fast-acting fentanyl formulations, which have pharmacokinetic profiles that closely match those of breakthrough pain episodes) and chemotherapy-induced neuropathic pain, which affects around one third of patients who receive chemotherapy. Finally, the point is made that medical education should place a greater emphasis on pain therapy, both at undergraduate and postgraduate level.

Managing chronic pain in elderly patients requires a CHANGE of approach.

In many countries, the number of elderly people has increased rapidly in recent years and this is expected to continue; it has been predicted that almost a quarter of the population in the European Union will be over 65 years of age in 2035. Many elderly people suffer from chronic pain but it is regularly under-treated, partly because managing these patients is often complex. This paper outlines the extent of untreated pain in this population and the consequent reduction in quality of life, before articulating the reasons why it is poorly or inaccurately diagnosed. These include the patient's unwillingness to complain, atypical pain presentations, multiple morbidities and cognitive decline. Successful pain management depends upon accurate diagnosis, which is based upon a complete history and thorough physical examination, as well as an assessment of psychosocial functioning. Poor physician/patient communication can be improved by using standardized instruments to establish individual treatment targets and measure progress towards them. User-friendly observational instruments may be valuable for patients with dementia. In line with the widely accepted biopsychosocial model of pain, a multidisciplinary approach to pain management is recommended, with pharmacotherapy, psychological support, physical rehabilitation and interventional procedures available if required. Declining organ function and other physiological changes require lower initial doses of analgesics and less frequent dosing intervals, and the physician must be aware of all medications that the patient is taking, in order to avoid drug/drug interactions. Non-adherence to treatment is common, and various strategies can be employed to improve it; involving the elderly patient's caregivers and family, using medication systems such as pill-boxes, or even sending text messages. In the long term, the teaching of pain medicine needs to be improved--particularly in the use of opioids--both at undergraduate level and after qualification.

3,5-Di-t-butyl catechol is a potent human ryanodine receptor 1 activator, not suitable for the diagnosis of malignant hyperthermia susceptibility.

3,5-Di-t-butyl catechol (DTCAT) releases Ca(2+) from rat skeletal muscle sarcoplasmic reticulum (SR) vesicles. Hence, it is a candidate for use as a substitute for halothane or caffeine in the in vitro contracture test for the diagnosis of susceptibility to malignant hyperthermia (MH). To characterize the effect of DTCAT at cell level, Ca(2+) release experiments were performed on cultured, human skeletal muscle myotubes using the fluorescent Ca(2+) indicator fura2-AM. DTCAT was also assayed in the in vitro contracture test on human skeletal muscle bundles obtained from individuals diagnosed susceptible (MHS), normal (MHN) or equivocal for halothane (MHEH) and compared to the standard test substances caffeine and halothane. DTCAT increased, in a concentration-dependent manner and with a higher efficacy as compared to caffeine, the free, intracellular Ca(2+) levels of cultured MHN and MHS skeletal muscle myotubes. This effect was similar in both types of myotubes and involved the release of Ca(2+) from SR stores as well as Ca(2+)-influx from the extracellular space. Inhibition of ryanodine receptors either with ryanodine or with ruthenium red markedly reduced DTCAT-induced increase in intracellular Ca(2+) concentration while abolishing that induced by caffeine. In MHN skeletal muscle bundles, DTCAT induced contractures with an EC(50) value of 160 ± 91 µM. However, the sensitivity of MHS or MHEH muscles to DTCAT was similar to that of MHN muscles. In conclusion, DTCAT is not suitable for the diagnosis of MH susceptibility due to its failure to discriminate between MHN and MHS muscles.

Tapentadol in the management of chronic low back pain: a novel approach to a complex condition?

Chronic pain affects approximately 1 in 5 people in Europe, and around half of sufferers receive inadequate pain management. The most common location is the lower back. Pharmacological treatment of this condition is challenging because of the range of causative mechanisms and the difficulty of balancing analgesic efficacy and tolerability. An international panel of clinical pain specialists met in September, 2009, to discuss the treatment of chronic low back pain, and to review preclinical and clinical data relating to the new analgesic, tapentadol. A lack of consensus exists on the best treatment for low back pain. The range of regularly prescribed pharmacological agents extends from nonopioids (paracetamol, NSAIDs, and COX-2 inhibitors) to opioids, antidepressants and anticonvulsants. Pain relief may be compromised, however, by an undetected neuropathic component or intolerable side effects. Treatment is potentially life-long and effective analgesics are urgently needed, with demonstrable long-term safety. Combining separate agents with different mechanisms of action could overcome the limitations of present pharmacological therapy, but clinical evidence for this approach is currently lacking. Tapentadol combines µ-opioid agonism with noradrenaline reuptake inhibition in a single molecule. There is strong evidence of synergistic antinociception between these two mechanisms of action. In preclinical and clinical testing, tapentadol has shown efficacy against both nociceptive and neuropathic pain. Preclinical data indicate that tapentadol's µ-opioid agonism makes a greater contribution to analgesia in acute pain, while noradrenaline reuptake inhibition makes a greater contribution in chronic neuropathic pain models. Tapentadol also produces fewer adverse events than oxycodone at equianalgesic doses, and thus may have a 'µ-sparing effect'. Current evidence indicates that tapentadol's efficacy/tolerability ratio may be better than those of classical opioids. However, further research is needed to establish its role in pain management.

Pharmacokinetics of intranasal fentanyl spray in patients with cancer and breakthrough pain.

OBJECTIVE: This study reports the pharmacokinetics, tolerability, and safety of an intranasalfentanyl spray (INFS) in patients with cancer and breakthrough pain (BTP). DESIGN: A randomized, open-label, two-period, crossover trial. PATIENTS: Nineteen adult patients (mean 57.8 years) with BTP, receiving opioid treatment for chronic background pain, from clinical departments in Austria, France, and Norway entered and completed the study. INTERVENTION: Patients were randomly assigned to receive one of six INFS dose sequences: 50/100, 100/50, 50/200, 200/50, 100/200, and 200/100 microg. INFS was administered as a single dose in one nostril. Each dose was separated by a minimum of 48 hours. MAIN OUTCOME MEASURE: Plasma fentanyl concentrations were measured by high-performance liquid chromatography and tandem mass spectrometry from blood samples obtained at 0 (predose) and frequently up to 300 minutes after INFS administration. Blood pressure, peripheral oxygen saturation, and respiratory rate were assessed eight times during each of the two treatment periods. RESULTS: Mean fentanyl plasma concentrations increased in a dose-dependent manner, peaking for all fentanyl doses 9-15 minutes after INFS administration. Median T(max) values were 15, 12, and 15 minutes for the 50, 100, and 200 microg doses of INFS, respectively. Mean (SD) values for C(max) were 351 (+/- 226), 595 (+/- 400), and 1195 (+/- 700) pg/mL, respectively, indicating dose-proportionality. Six patients (31.6 percent) experienced adverse events during the treatment period, the majority being mild in severity. CONCLUSION: INFS at doses of 50, 100, and 200 microg showed a short T(max) and was well tolerated in patients with cancer. These results support INFS use in patients with cancer suffering from BTP.

Efficacy and tolerability of intranasal fentanyl spray 50 to 200 microg for breakthrough pain in patients with cancer: a phase III, multinational, randomized, double-blind, placebo-controlled, crossover trial with a 10-month, open-label extension treatment period.

OBJECTIVE: This trial investigated the efficacy and long-term tolerability of intranasal fentanyl spray (INFS) 50 to 200 microg in the treatment of breakthrough pain in opioid-tolerant patients with cancer. METHODS: This Phase III, double-blind, randomized, placebo-controlled, crossover trial was conducted at pain centers, anesthesiology departments, palliative care units, and oncology clinics in Austria, Denmark, France, Germany, and Poland. Eligible patients were adults with cancer receiving a stable dose of long-term opioid treatment for the control of background pain. Patients were treated at home with their effective dose of INFS (50, 100, or 200 microg) or inactive spray (placebo) in a randomized sequence for 3 weeks, followed by a 10-month, open-label tolerability phase during which they received their effective dose of INFS. Throughout the study, patients were allowed to use their usual rescue medication, which was recorded in patient diaries. The primary efficacy end point was the pain intensity difference at 10 minutes after study drug administration (PID(10)), as assessed using an 11-point numeric rating scale (0 = no pain to 10 = worst pain imaginable). An effect size of 0.5 for PID was considered clinically relevant. The rate of response, defined as PID(10) >2, was also assessed. Adverse events (AEs) were recorded in patient diaries during the efficacy period and reported in monthly clinic visits and follow-up weekly telephone contacts during the extension period. RESULTS: In all, 120 patients were enrolled and achieved an effective dose; 113 were randomized and 111 were included in the intent-to-treat analysis set (56 men, 55 women; mean [SD] age, 60.6 [9.45] years; mean weight, 70.3 kg [men] and 65.3 kg [women]; white race, 107 [96.4%]; INFS 50 microg, 18; INFS 100 microg, 48; INFS 200 microg, 45; placebo, 110). PID(10) with INFS was 2-fold that with placebo (adjusted means, 2.36 vs 1.10; adjusted difference, 1.26 [greater than the clinically relevant difference of 0.5]; P < 0.001). Additional analysis revealed that the mean response rate with all 3 doses of INFS was 51.1% versus 20.9% with placebo. The prevalence of AEs was 22/111 (19.8%) during the efficacy period, during which the most frequently reported AEs were nausea (5 [4.5%]) and vertigo (2 [1.8%]). No serious AEs were considered related to the study drugs. In all, 108 patients entered the extension period, with a mean duration of exposure to INFS of 134.9 days. Progression of underlying malignant disease was the most common AE reported during this period (55 [50.9%]); this event was not considered treatment related. CONCLUSIONS: In these opioid-tolerant patients with cancer, INFS at doses of 50, 100, and 200 microg was associated with an onset of activity at 10 minutes and effective treatment of breakthrough pain compared with placebo. All doses were generally well tolerated and clinically efficacious.

Opioids and the management of chronic severe pain in the elderly: consensus statement of an International Expert Panel with focus on the six clinically most often used World Health Organization Step III opioids (buprenorphine, fentanyl, hydromorphone, methadone, morphine, oxycodone).

SUMMARY OF CONSENSUS: 1. The use of opioids in cancer pain: The criteria for selecting analgesics for pain treatment in the elderly include, but are not limited to, overall efficacy, overall side-effect profile, onset of action, drug interactions, abuse potential, and practical issues, such as cost and availability of the drug, as well as the severity and type of pain (nociceptive, acute/chronic, etc.). At any given time, the order of choice in the decision-making process can change. This consensus is based on evidence-based literature (extended data are not included and chronic, extended-release opioids are not covered). There are various driving factors relating to prescribing medication, including availability of the compound and cost, which may, at times, be the main driving factor. The transdermal formulation of buprenorphine is available in most European countries, particularly those with high opioid usage, with the exception of France; however, the availability of the sublingual formulation of buprenorphine in Europe is limited, as it is marketed in only a few countries, including Germany and Belgium. The opioid patch is experimental at present in U.S.A. and the sublingual formulation has dispensing restrictions, therefore, its use is limited. It is evident that the population pyramid is upturned. Globally, there is going to be an older population that needs to be cared for in the future. This older population has expectations in life, in that a retiree is no longer an individual who decreases their lifestyle activities. The "baby-boomers" in their 60s and 70s are "baby zoomers"; they want to have a functional active lifestyle. They are willing to make trade-offs regarding treatment choices and understand that they may experience pain, providing that can have increased quality of life and functionality. Therefore, comorbidities--including cancer and noncancer pain, osteoarthritis, rheumatoid arthritis, and postherpetic neuralgia--and patient functional status need to be taken carefully into account when addressing pain in the elderly. World Health Organization step III opioids are the mainstay of pain treatment for cancer patients and morphine has been the most commonly used for decades. In general, high level evidence data (Ib or IIb) exist, although many studies have included only few patients. Based on these studies, all opioids are considered effective in cancer pain management (although parts of cancer pain are not or only partially opioid sensitive), but no well-designed specific studies in the elderly cancer patient are available. Of the 2 opioids that are available in transdermal formulation--fentanyl and buprenorphine--fentanyl is the most investigated, but based on the published data both seem to be effective, with low toxicity and good tolerability profiles, especially at low doses. 2. The use of opioids in noncancer-related pain: Evidence is growing that opioids are efficacious in noncancer pain (treatment data mostly level Ib or IIb), but need individual dose titration and consideration of the respective tolerability profiles. Again no specific studies in the elderly have been performed, but it can be concluded that opioids have shown efficacy in noncancer pain, which is often due to diseases typical for an elderly population. When it is not clear which drugs and which regimes are superior in terms of maintaining analgesic efficacy, the appropriate drug should be chosen based on safety and tolerability considerations. Evidence-based medicine, which has been incorporated into best clinical practice guidelines, should serve as a foundation for the decision-making processes in patient care; however, in practice, the art of medicine is realized when we individualize care to the patient. This strikes a balance between the evidence-based medicine and anecdotal experience. Factual recommendations and expert opinion both have a value when applying guidelines in clinical practice. 3. The use of opioids in neuropathic pain: The role of opioids in neuropathic pain has been under debate in the past but is nowadays more and more accepted; however, higher opioid doses are often needed for neuropathic pain than for nociceptive pain. Most of the treatment data are level II or III, and suggest that incorporation of opioids earlier on might be beneficial. Buprenorphine shows a distinct benefit in improving neuropathic pain symptoms, which is considered a result of its specific pharmacological profile. 4. The use of opioids in elderly patients with impaired hepatic and renal function: Functional impairment of excretory organs is common in the elderly, especially with respect to renal function. For all opioids except buprenorphine, half-life of the active drug and metabolites is increased in the elderly and in patients with renal dysfunction. It is, therefore, recommended that--except for buprenorphine--doses be reduced, a longer time interval be used between doses, and creatinine clearance be monitored. Thus, buprenorphine appears to be the top-line choice for opioid treatment in the elderly. 5. Opioids and respiratory depression: Respiratory depression is a significant threat for opioid-treated patients with underlying pulmonary condition or receiving concomitant central nervous system (CNS) drugs associated with hypoventilation. Not all opioids show equal effects on respiratory depression: buprenorphine is the only opioid demonstrating a ceiling for respiratory depression when used without other CNS depressants. The different features of opioids regarding respiratory effects should be considered when treating patients at risk for respiratory problems, therefore careful dosing must be maintained. 6. Opioids and immunosuppression: Age is related to a gradual decline in the immune system: immunosenescence, which is associated with increased morbidity and mortality from infectious diseases, autoimmune diseases, and cancer, and decreased efficacy of immunotherapy, such as vaccination. The clinical relevance of the immunosuppressant effects of opioids in the elderly is not fully understood, and pain itself may also cause immunosuppression. Providing adequate analgesia can be achieved without significant adverse events, opioids with minimal immunosuppressive characteristics should be used in the elderly. The immunosuppressive effects of most opioids are poorly described and this is one of the problems in assessing true effect of the opioid spectrum, but there is some indication that higher doses of opioids correlate with increased immunosuppressant effects. Taking into consideration all the very limited available evidence from preclinical and clinical work, buprenorphine can be recommended, while morphine and fentanyl cannot. 7. Safety and tolerability profile of opioids: The adverse event profile varies greatly between opioids. As the consequences of adverse events in the elderly can be serious, agents should be used that have a good tolerability profile (especially regarding CNS and gastrointestinal effects) and that are as safe as possible in overdose especially regarding effects on respiration. Slow dose titration helps to reduce the incidence of typical initial adverse events such as nausea and vomiting. Sustained release preparations, including transdermal formulations, increase patient compliance.

No carnitine palmitoyltransferase deficiency in skeletal muscle in 18 malignant hyperthermia susceptible individuals.

Malignant hyperthermia is a rare, potentially life threatening pharmacogenetic disorder triggered by volatile anaesthetics and depolarizing muscle relaxants. The clinical picture comprises rhabdomyolysis, metabolic and respiratory acidosis, and hyperthermia. Carnitine palmitoyltransferase II deficiency is a metabolic myopathy affecting the transport of fatty acids into the mitochondria, leading to impaired energy supply under stressful conditions resulting in muscle weakness and rhabdomyolysis. It was postulated in a previous study that some patients with the MH phenotype have a carnitine palmitoyltransferase deficiency. To investigate a potential association, we tested 18 individuals with proven MH susceptibility for impairment of carnitine palmitoyltransferase enzyme activity in muscle. Enzyme activity was normal in all individuals tested indicating no impairment of the CPT system in this sample of malignant hyperthermia susceptible individuals. Thus our data do not support the hypothesis that susceptibility to malignant hyperthermia has an effect on the carnitine palmitoyltransferase enzyme system.

Perioperative auricular electroacupuncture has no effect on pain and analgesic consumption after third molar tooth extraction.

BACKGROUND: Auricular acupuncture (AA) has been shown to alleviate acute and chronic pain. We investigated the effects of auricular electroacupuncture (AE) on pain and analgesic drug consumption in the first 48 h after unilateral mandibular third molar tooth extraction under local anesthesia in a prospective, randomized, double-blind, placebo-controlled study in 149 patients. METHODS: Patients received either AA with electrical stimulation (AE, n = 76) or without (AA, n = 37) electrical stimulation at an alternating frequency of 2/100 Hz or a sham AE with metal plates instead of needles and no electrical stimulation, no-needle (NN, n = 36) at the AA points 1 (tooth), 55 (Shen men) and 84 (mouth) during the entire study period. Regularly rated pain intensity (five-point verbal rating scale), consumption of acetaminophen 500 mg tablets and additional rescue medication with mefenamic acid 500 mg were assessed. RESULTS: The median fraction of time when pain was rated as moderate or worse (upper and lower quartile): AE: 33% (12%, 64%), AA: 22% (6%, 56%), NN: 30% (7%, 53%) did not differ significantly among the treatment groups. There were no significant differences in mean number of acetaminophen 500 mg tablets (range): AE: 5.2 (0-12), AA: 4.6 (0-11), NN: 5.4 (0-10) or percentage of patients requiring additional mefenamic acid: AE: 19%, AA: 18%, NN: 19%. CONCLUSION: We conclude that neither AE nor AA alone reduce either pain intensity or analgesic consumption in a molar tooth extraction model of acute pain.