Guy Hans

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)

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.

Behavioral signs of acute pain produced by application of endothelin-1 to rat sciatic nerve

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 μM) applied to the epineurial surface of rat sciatic nerve produced reliable, robust, unilateral hindpaw flinching lasting 60 min. Preemptive 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 (ETA) receptor antagonist, also blocked ET-1-induced hindpaw flinching establishing that pain behavior induced by ET-1 application to rat sciatic nerve is ETA receptor mediated.

Topical 5% lidocaine (lignocaine) medicated plaster treatment for post-herpetic neuralgia: results of a double-blind, placebo-controlled, multinational efficacy and safety trial

AbstractBackground and objective: Post-herpetic neuralgia (PHN) is a distressing neuropathic pain condition mainly affecting elderly patients. Neuropathic pain symptoms can be of a burning, shooting and stabbing nature, and may continue for prolonged periods and are often poorly controlled by polymedication. The aim of this study was to evaluate the analgesic efficacy and safety of topical analgesic treatment (5% lidocaine [lignocaine] medicated plaster) compared with placebo plaster in patients with PHN. Methods: This was a double-blind, placebo plaster-controlled, parallel-group, multicentre study employing enriched enrolment with randomized withdrawal methodology. After an initial 8-week open-label, active run-in phase, responders entered a 2-week randomized, double-blind, placebo-controlled phase. The study was conducted at 33 outpatient investigational centres in 12 European countries. Patients with PHN were selected who were aged ≥50 years, had experienced neuropathic pain persisting for ≥3 months after rash healing, and had a mean pain intensity of ≥4 on an 11-point numerical rating scale. A total of 265 patients entered the open-label phase and subsequently a pre-defined number of 71 patients entered the randomized phase. Patients applied up to three 5% lidocaine medicated plasters for up to 12 hours per day. The primary endpoint of the study was time-to-exit due to a ≥2-point reduction in pain relief on two consecutive days of plaster application using a 6-point verbal rating scale. Results: Of the 265 patients entering the run-in phase, 51.7% achieved at least moderate pain relief. In the double-blind phase (full analysis set, n = 71), median times-to-exit were 13.5 (range 2–14) and 9.0 (range 1–14) days for lidocaine and placebo plaster groups, respectively (p = 0.151). For per-protocol patients (n = 34), median time-to-exit was 14.0 (range 3–14) and 6.0 (range 1–14) days for lidocaine and placebo plaster groups, respectively (p = 0.0398). Drug-related adverse events occurred in 13.6% of patients. Treatment with 5% lidocaine medicated plaster was associated with improvements in pain, allodynia, quality of life and sleep measures. Conclusions: This study adds to a growing body of evidence that the 5% lidocaine medicated plaster can be considered a valuable treatment option for patients with PHN, providing beneficial effects on pain, allodynia, quality of life and sleep, with minimal adverse effects.

In the mind or in the brain? Scientific evidence for central sensitisation in chronic fatigue syndrome

Eur J Clin Invest 2011

Peripheral Input and Its Importance for Central Sensitization

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. Ann Neurol 2013;74:630–636

Efficacy and tolerability of a 5% lidocaine medicated plaster for the topical treatment of post-herpetic neuralgia: results of a long-term study

ABSTRACT Objective: Evaluation of long-term efficacy and safety of the 5% lidocaine medicated plaster for neuropathic pain symptoms in patients with post-herpetic neuralgia (PHN). Materials and methods: Design – a 12-month, open-label, phase III study with an open-label extension conducted at 34 outpatient clinics in 12 European countries. Patients – aged ≥50 years, newly recruited (average pain intensity ≥4) or pre-treated with the 5% lidocaine medicated plaster in a previous study. Interventions – application of up to three 5% lidocaine medicated plasters dependent upon size of the painful area for up to 12 hours per day. Outcome measures – efficacy measures included patients’ recall of pain relief and pain intensity in the previous week. Adverse events (AEs) were also reported. Results: 249 patients participated in the 12-month study, 247 were analysed (full analysis set, FAS). Newly recruited patients had a mean average pain intensity (11-point numerical rating scale [NRS]) of 5.9 ± 1.4 at baseline, which decreased to 3.9 ± 1.6 at week 12 and remained stable at 3.9 ± 2.3 until the end of the 12-month study. In pre-treated patients, pain intensity decreased further from baseline (3.9 ± 1.9) to study end (3.4 ± 2.0). Pain relief values were consistent with pain intensity reductions and were sustained in patients continuing treatment in the extension phase (mainly ≥24 months treatment in total). The most common AEs tended to be infections such as bronchitis and nasopharyngitis. Forty-eight drug-related adverse events (DRAEs), mainly mild to moderate localised skin reactions, occurred in 31 (12.4%) patients in the first 12 months. The profile of DRAEs was similar in the extension phase. Conclusions: This study suggests that long-term treatment with the 5% lidocaine medicated plaster may provide substantial and maintained reductions in pain intensity, and that it is continuously well tolerated in patients suffering from peripheral neuropathic pain associated with previous herpes zoster infection. These findings support the use of the 5% lidocaine medicated plaster as one of the first-line therapies in this population.

Behavioral assessment of facial pain in rats : face grooming patterns after painful and non-painful sensory disturbances in the territory of the rat's infraorbital nerve

&NA; Noxious stimulation of the rats 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.

Opioid rotation in the management of chronic pain: where is the evidence?

The management of chronic pain remains a challenge because of its complexity and unpredictable response to pharmacological treatment. In addition, accurate pain management may be hindered by the prejudice of physicians and patients that strong opioids, classified as step 3 medications in the World Health Organization ladder for cancer pain management, are reserved for the end stage of life. Recent information indicates the potential value of strong opioids in the treatment of chronic nonmalignant pain. There are, up until now, insufficient data to provide indications about which opioid to use to initiate treatment or the dose to be used for any specific pain syndrome. The strong inter‐patient variability in opioid receptor response and in the pharmacokinetic and pharmacodynamic behavior of strong opioids justifies an individual selection of the appropriate opioid and stepwise dose titration. Clinical experience shows that switching from one opioid to another may optimize pain control while maintaining an acceptable side effect profile or even improving the side effects. This treatment strategy, described as opioid rotation or switch, requires a dose calculation for the newly started opioid. Currently, conversion tables and equianalgesic doses are available. However, those recommendations are often based on data derived from studies designed to evaluate acute pain relief, and sometimes on single dose studies, which reduces this information to the level of an indication. In daily practice, the clinician needs to titrate the optimal dose during the opioid rotation from a reduced calculated dose, based on the clinical response of the patient. Further research and studies are needed to optimize the equianalgesic dosing tables.

Levobupivacaine combined with sufentanil and epinephrine for intrathecal labor analgesia: a comparison with racemic bupivacaine.

We performed a randomized, double-blinded study to compare levobupivacaine with racemic bupivacaine for labor analgesia. Eighty term parturients received either levobupivacaine 0.125% or racemic bupivacaine 0.125%, to which was added sufentanil 0.75 &mgr;g/mL and epinephrine 1.25 &mgr;g/mL. As part of a combined spinal-epidural procedure, 2 mL of this mixture was initially injected intrathecally, and the same solutions were subsequently administered epidurally. For both combinations, onset until the first painless contraction was 4 to 5 min. Most patients were pain free during the second contraction. The duration of initial spinal analgesia was 93.5 ± 20 min and 94.7 ± 31 min for levobupivacaine and racemic bupivacaine, respectively. The duration of analgesia for the first epidural top-up dose was also similar in the two groups. Total local anesthetic requirements during labor were not different. The only major difference observed was the absence of motor impairment in levobupivacaine-treated parturients as compared with the Racemic Bupivacaine group, in which the incidence of a Bromage-1 motor block was 34%. Other side effects and obstetric or neonatal outcomes were not different between groups. Intrathecal levobupivacaine has a similar clinical profile as racemic bupivacaine, but at equal doses it produced less motor block.

The diagnosis and management of neuropathic pain in daily practice in Belgium: an observational study

BackgroundThis open, multicentre, observational survey investigated how physicians diagnose neuropathic pain (NeP) by applying the Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) scale, and how neuropathic pain conditions are managed in daily practice in Belgium.MethodsPhysicians were asked to complete the Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) scale for diagnosing NeP, and to fill out a questionnaire regarding the management of NeP, together with a questionnaire evaluating the impact of pain on sleep and daily life. Data on 2,480 pain patients were obtained. A LANSS score ≥ 12 (meaning NeP is most probably present) was reported for 1,163 patients. Pathologies typically associated with NeP scored above 12 on the LANSS scale, contrary to pathologies generally considered as being of non-neuropathic origin.ResultsOver 90% of the patients with a LANSS score ≥ 12 reported that the pain impaired sleep. A high impact on social, family and professional life was also recorded. Additional examinations were performed in 89% of these patients. Most patients were taking multiple drugs, mainly paracetamol and non-steroidal anti-inflammatory drugs, indicating that physicians generally tend to follow treatment guidelines of chronic nociceptive pain, rather than the specific ones for NeP. Specific neuropathic guidelines rather recommend the use of anti-epileptic drugs, tricyclic antidepressants or weak opioids as first-line treatment.ConclusionIn our survey, application of the LANSS scale lead to pronounced treatment simplification with fewer drug combinations. Awareness about NeP as well as its specific treatment recommendations should be raised among healthcare providers. We concluded that the LANSS screening scale is an interesting tool to assist physicians in detecting NeP patients in routine clinical care.