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...

Many pain states begin with damage to tissue and/or nerves in the periphery, leading to enhanced transmitter release within the spinal cord and central sensitization. Manifestations of this central sensitization are windup and long-term potentiation. Hyperexcitable spinal neurons show reduced thresholds, greater evoked responses, increased receptive field sizes, and ongoing stimulus-independent activity; these changes probably underlie the allodynia, hyperalgesia, and spontaneous pain seen in patients. Central sensitization is maintained by continuing input from the periphery, but also modulated by descending controls, both inhibitory and facilitatory, from the midbrain and brainstem. The projections of sensitized spinal neurons to the brain, in turn, alter the processing of painful messages by higher centers. Several mechanisms contribute to central sensitization. Repetitive activation of primary afferent C fibers leads to a synaptic strengthening of nociceptive transmission. It may also induce facilitation of non-nociceptive Aβ fibers and nociceptive Aδ fibers, giving rise to dynamic mechanical allodynia and mechanical hyperalgesia. In postherpetic neuralgia and complex regional pain syndrome, for example, these symptoms are maintained and modulated by peripheral nociceptive input. Diagnosing central sensitization can be particularly difficult. In addition to the medical history, quantitative sensory testing and functional magnetic resonance imaging may be useful, but diagnostic criteria that include both subjective and objective measures of central augmentation are needed. Mounting evidence indicates that treatment strategies that desensitize the peripheral and central nervous systems are required. These should generally involve a multimodal approach, so that therapies may target the peripheral drivers of central sensitization and/or the central consequences.

Neurobehavioral and neurophysiological actions of the peptide endothelin-1 (ET-1) were investigated after subcutaneous plantar hindpaw injections in adult male Sprague Dawley rats. Hindpaw flinching developed within minutes after ET-1 (8-16 nmol) injection, peaked at 30 min, lasted for 60 min, and was strongly inhibited by the endothelin-A (ET A ) receptor antagonist, BQ-123 (3.2 M). In separate experiments, impulse activity of single, physiologically characterized sensory C-, A␦-, and A␤-fibers was recorded from the sciatic nerve in anesthetized rats after subcutaneous injections of endothelin-1 (1-20 nmol), alone or together with BQ-123 (3.2 M), into the plantar hindpaw receptive fields of these units. All nociceptive C-fibers (31 of 33 C-fibers studied) were excited by ET-1 (1-20 nmol) in a dosedependent manner. For doses of 16-20 nmol, the mean latency for afferent activation after injection of ET-1 was 3.16 Ϯ 0.31 min, and the mean and maximum response frequency were 2.02 Ϯ 0.48 impulses (imp)/sec and 14.0 Ϯ 3.2 imp/sec, respectively. All 10 nociceptive A␦-fibers (of 12 A␦-fibers studied) also responded to 1-20 nmol of ET-1 in a dose-dependent manner with a mean latency of 3.5 Ϯ 0.12 min and mean response frequency of 3.3 Ϯ 2.3 imp/sec. In contrast, most A␤-fibers (9 of 12) did not respond to ET-1. BQ-123, when coinjected with ET-1, blocked ET-1-induced activation in all Cand A␦-fibers tested. These data demonstrate that subcutaneous administration of ET-1 to the rat plantar hindpaw produces pain-like behavior and selective excitation of nociceptive fibers through activation of ET A receptors. Key words: excitability; peripheral nerve; algogenic; C-fiber; nociceptor; cancerPain is a frequent and disabling consequence of metastatic prostate and breast cancer in humans. The cause of this pain is unknown but may involve mediator-dependent signaling by tumor cells to spinal nerve roots. One candidate mediator, the potent vasoconstrictive peptide and mitogen endothelin-1 (ET-1), is secreted in high concentrations by metastatic prostate and breast cancer cells and is known to induce pain-like behavior in animals and pain in humans (Ferreira et al

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We examined whether endothelin-1 (ET-1), a potent vasoconstrictive peptide secreted in high concentration by metastatic prostate cancer cells, produces endothelin receptor-dependent pain behavior when applied to rat sciatic nerve. ET-1 (200-800 microM) applied to the epineurial surface of rat sciatic nerve produced reliable, robust, unilateral hindpaw flinching lasting 60 min. Pre-emptive systemic morphine completely blocked this effect in a naloxone-reversible manner, suggesting that this behavior was pain-related. Equipotent doses of epineurially applied epinephrine had no effect, suggesting that ET-1 effects are on tissue sites other than sciatic nerve microvessels. Prior and co-administration of BQ-123, an endothelin-A (ET(A)) receptor antagonist, also blocked ET-1-induced hindpaw flinching establishing that pain behavior induced by ET-1 application to rat sciatic nerve is ET(A) receptor mediated.

Background Central sensitisation entails several top-down and bottom-up mechanisms, all contributing to the hyperresponsiveness of the central nervous system to a variety of inputs. In the late nineties, it was first hypothesised that chronic fatigue syndrome (CFS) is characterised by hypersensitivity of the central nervous system (i.e. central sensitisation). Since then, several studies have examined central sensitisation in patients with CFS. This study provides an overview of such studies.

Raising awareness about possible neurological complications and adoption of safety measures recommended by the work group aim at reducing the risks for these devastating events.

Noxious stimulation of the rat's face evokes intense face grooming with face wash strokes almost exclusively directed to the stimulated area (e.g. Clavelou et al., Neurosci. Lett., 14 (1989) 3263-3270). Similar asymmetric face grooming behavior has been observed after transection (Berridge and Fentress, J. Neurosci., 6 (1986) 325-330) and chronic constriction of the infraorbital nerve (Vos et al., J. Neurosci., 14 (1994) 2708-2723). In the present study, the relation between unilateral facial pain and asymmetric face grooming was experimentally studied in normal, intact rats: face grooming patterns evoked by non-painful sensory disturbances in the territory of the infraorbital nerve (i.c. unilateral vibrissae clipping, anesthetic infraorbital nerve blockade, application of mineral oil on vibrissae) were compared to those evoked by noxious facial stimulation (s.c. formalin injection in mystacial pad) and those observed in unstimulated control rats, using video-analysis. Only formalin-injected rats displayed significantly more face grooming activity directed to the affected infraorbital nerve territory than unstimulated control rats. Non-painful sensory disturbances (especially mineral oil application) induced an initial bout of directed face grooming; this response was transient and short-lasting. These observations suggest that directed face grooming can be used as a sign of unilateral facial pain in freely moving rodents; unilateral non-painful facial sensory disturbances do not lead to intense and persistent directed face grooming.