Background
Pharmacotherapy remains an important modality for the treatment of neuropathic pain. However, as monotherapy current drugs are associated with limited efficacy and dose-related side effects. Combining two or more different drugs may improve analgesic efficacy and, in some situations, reduce overall side effects (e.g. if synergistic interactions allow for dose reductions of combined drugs).

Objectives
This review evaluated the efficacy, tolerability and safety of various drug combinations for the treatment of neuropathic pain.

Search methods
We identified randomised controlled trials (RCTs) of various drug combinations for neuropathic pain from CENTRAL, MEDLINE, EMBASE and handsearches of other reviews and trial registries. The most recent search was performed on 9 April 2012.

Selection criteria
Double-blind, randomised studies comparing combinations of two or more drugs (systemic or topical) to placebo and/or at least one other comparator for the treatment of neuropathic pain.

Data collection and analysis
Data extracted from each study included: proportion of participants a) reporting ≥ 30% pain reduction from baseline OR ≥ moderate pain relief OR ≥ moderate global improvement; b) dropping out of the trial due to treatment-emergent adverse effects; c) reporting each specific adverse effect (e.g. sedation, dizziness) of ≥ moderate severity. The primary comparison of interest was between study drug(s) and one or both single-agent comparators. We combined studies if they evaluated the same drug class combination at roughly similar doses and durations of treatment. We used RevMan 5 to analyse data for binary outcomes.

Main results
We identified 21 eligible studies: four (578 participants) evaluated the combination of an opioid with gabapentin or pregabalin; two (77 participants) evaluated an opioid with a tricyclic antidepressant; one (56 participants) of gabapentin and nortriptyline; one (120 participants) of gabapentin and alpha-lipoic acid, three (90 participants) of fluphenazine with a tricyclic antidepressant; three (90 participants) of an N-methyl-D-aspartate (NMDA) blocker with an agent from a different drug class; five (604 participants) of various topical medications; one (313 participants) of tramadol with acetaminophen; and another one (44 participants) of a cholecystokinin blocker (L-365,260) with morphine. The majority of combinations evaluated to date involve drugs, each of which share some element of central nervous system (CNS) depression (e.g. sedation, cognitive dysfunction). This aspect of side effect overlap between the combined agents was often reflected in similar or higher dropout rates for the combination and may thus substantially limit the utility of such drug combinations. Meta-analysis was possible for only one comparison of only one combination, i.e. gabapentin + opioid versus gabapentin alone. This meta-analysis involving 386 participants from two studies demonstrated modest, yet statistically significant, superiority of a gabapentin + opioid combination over gabapentin alone. However, this combination also produced significantly more frequent side effect-related trial dropouts compared to gabapentin alone.

Authors' conclusions
Multiple, good-quality studies demonstrate superior efficacy of two-drug combinations. However, the number of available studies for any one specific combination, as well as other study factors (e.g. limited trial size and duration), preclude the recommendation of any one specific drug combination for neuropathic pain. Demonstration of combination benefits by several studies together with reports of widespread clinical polypharmacy for neuropathic pain surely provide a rationale for additional future rigorous evaluations. In order to properly identify specific drug combinations which provide superior efficacy and/or safety, we recommend that future neuropathic pain studies of two-drug combinations include comparisons with placebo and both single-agent components. Given the apparent adverse impact of combining agents with similar adverse effect profiles (e.g. CNS depression), the anticipated development and availability of non-sedating neuropathic pain agents could lead to the identification of more favourable analgesic drug combinations in which side effects are not compounded.

Combination pharmacotherapy for the treatment of neuropathic pain in adults

Introduction: The use of intrathecal (IT) infusion of analgesic medications to treat patients with chronic refractory pain has increased since its inception in the 1980s, and the need for clinical research in IT therapy is ongoing. The Polyanalgesic Consensus Conference (PACC) panel of experts convened in 2000, 2003, and 2007 to make recommendations on the rational use of IT analgesics based on preclinical and clinical literature and clinical experiences.

Methods:  The PACC panel convened again in 2011 to update the standard of care for IT therapies to reflect current knowledge gleaned from literature and clinical experience. A thorough literature search was performed, and information from this search was provided to panel members. Analysis of published literature was coupled with the clinical experience of panel members to form recommendations regarding the use of IT analgesics to treat chronic pain.

Results:  After a review of literature published from 2007 to 2011 and discussions of clinical experience, the panel created updated algorithms for the rational use of IT medications for the treatment of neuropathic pain and nociceptive pain.

Conclusions:  The advent of new algorithmic tracks for neuropathic and nociceptive pain is an important step in improving patient care. The panel encourages continued research and development, including the development of new drugs, devices, and safety recommendations to improve the care of patients with chronic pain.

/pdf/polyanalgesic-consensus-conference-2012-recommendations-for-vxi6sx4mjx.pdf

Polyanalgesic Consensus Conference 2012: recommendations for the management of pain by intrathecal (intraspinal) drug delivery: report of an interdisciplinary expert panel.

Interaction of mitoxantrone with human serum albumin: spectroscopic and molecular modeling studies.

Background Intervertebral disc herniation, spinal stenosis, intervertebral disc degeneration without disc herniation, and post lumbar surgery syndrome are the most common diagnoses of chronic persistent low back and lower extremity symptoms, resulting in significant economic, societal, and health care impact. Epidural injections are one of the most commonly performed interventions in the United States in managing chronic low back pain. However the evidence is highly variable among different techniques utilized - namely interlaminar, caudal, and transforaminal - and for various conditions, namely - intervertebral disc herniation, spinal stenosis, and discogenic pain without disc herniation or radiculitis. Multiple systematic reviews conducted in the evaluation of the effectiveness of interlaminar epidural injections have been marred with controversy. Consequently, the debate continues with regards to the effectiveness, indications, and medical necessity of interlaminar epidural injections. Study design A systematic review of lumbar interlaminar epidural injections with or without steroids. Objective To evaluate the effect of lumbar interlaminar epidural injections with or without steroids in managing various types of chronic low back and lower extremity pain emanating as a result of disc herniation or radiculitis, spinal stenosis, and chronic discogenic pain. Methods The available literature on lumbar interlaminar epidural injections with or without steroids in managing various types of chronic low back pain with or without lower extremity pain was reviewed. The quality assessment and clinical relevance criteria utilized were the Cochrane Musculoskeletal Review Group criteria as utilized for interventional techniques for randomized trials and the criteria developed by the Newcastle-Ottawa Scale criteria for observational studies. The level of evidence was classified as good, fair, or limited based on the quality of evidence developed by the U.S. Preventive Services Task Force (USPSTF). Data sources included relevant literature identified through searches of PubMed and EMBASE from 1966 to December 2011, and manual searches of the bibliographies of known primary and review articles. Outcome measures The primary outcome measure was pain relief (short-term relief = up to 6 months and long-term > 6 months). Secondary outcome measures were improvement in functional status, psychological status, return to work, and reduction in opioid intake. Results Overall, 82 lumbar interlaminar trials were identified. All non-randomized studies without fluoroscopy and randomized trials not meeting the inclusion criteria were excluded. Overall, 15 randomized trials and 11 non-randomized studies were included in the analysis. Analysis was derived mainly from fluoroscopically-guided randomized trials and non-randomized studies. The evidence is good for radiculitis secondary to disc herniation with local anesthetics and steroids, fair with local anesthetic only; whereas it is fair for radiculitis secondary to spinal stenosis with local anesthetic and steroids, and fair for axial pain without disc herniation with local anesthetic with or without steroids, with fluoroscopically-guided epidural injections. Limitations The limitations of this study include that we were unable to perform meta-analysis for disc herniation, and the paucity of evidence for discogenic pain and spinal stenosis. Further, methodological criteria have been highly variable along with sample sizes. The studies were heterogenous. Conclusion The evidence based on this systematic review is good for lumbar epidural injections under fluoroscopy for radiculitis secondary to disc herniation with local anesthetic and steroids, fair with local anesthetic only; whereas it is fair for radiculitis secondary to spinal stenosis with local anesthetic and steroids, and fair for axial pain without disc herniation with local anesthetic with or without steroids.

/pdf/the-effectiveness-of-lumbar-interlaminar-epidural-injections-4gvmoswr4j.pdf

The effectiveness of lumbar interlaminar epidural injections in managing chronic low back and lower extremity pain

Pharmacological and non-pharmacological treatments for neuropathic pain: Systematic review and French recommendations.

Summary
Laryngeal mask airway (LMA) is increasingly being used in children as it is less invasive compared to endotracheal intubation and causes less discomfort in the postoperative period However, some concerns remained about its safety during positive pressure ventilation in children

In a prospective randomized trial, 100 ASA I and II children weighing between 10-20 kg in the range of 2-10 years of age, scheduled for elective surgery were randomly allocated to one of the two groups of 50 patients each The efficacy of LMA in children during positive pressure ventilation, its haemodynamic changes and postoperative complications were compared to endotracheal intubation Insertion of LMA was easier in 94% patients while endotracheal intubation was done easily in 53% of patients only (p<005) The changes in haemodynamic parameters were significantly higher after endotracheal intubation as compared to LMA placement Furthermore these changes persisted for longer duration after endotracheal intubation in comparison to LMA insertion (5 min vs 3 min) Incidence of postoperative complications ie bronchospasm, laryngospasm and soft tissue trauma was significantly higher (p<005) after endotracheal intubation as compared to LMA insertion

To conclude, the laryngeal mask airway is a suitable alternative to endotracheal intubation for positive pressure ventilation in children

A Study of the Use of Laryngeal Mask Airway (LMA) in Children and its Comparison with Endotracheal Intubation

Background Post herpetic neuralgia is a chronic neuropathic pain syndrome which remains one of the most difficult pain disorders to treat. Epidural injection of methylprednisolone with or without local anesthetic provides relief for neuralgia for a short duration only. Recent studies have shown a promising anti nociceptive effect for intrathecal midazolam, a water soluble benzodiazepine, due to its interaction with benzodiazepine-GABA-A receptor complex within the spinal cord. Study design A randomized, double blind study was conducted at 2 different centers in India. Setting Two different interventional pain practice centers in India. Objectives To quantify the effectiveness of a single intrathecal injection of midazolam 2 mg with and without epidural methylprednisolone 60 mg for management of pain and allodynia in 150 adult patients with postherpetic neuralgia of 3-6 months duration involving lumbosacral dermatomes. Methods Patients in Group M-0 (n=50) received epidural methylprednisolone (60 mg), patients in group M-1 (n=50) received midazolam 2 mg in the intrathecal space while patients in Group M-2 (n=50) received methylprednisolone (60 mg) in the epidural space plus midazolam 2 mg in the intrathecal space. Results The administration of intrathecal midazolam (2 mg) provided short term improvement in post herpetic neuralgia similar to epidural methylprednisolone. However, the combination of intrathecal midazolam with epidural methylprednisolone resulted in prolonged duration of analgesia in patients with post herpetic neuralgia. The need for analgesics was also significantly less in patients who received the combination compared to those who received either intrathecal midazolam or epidural methylprednisolone. No serious adverse effect was reported with the use of intrathecal midazolam except a mild degree of sedation. Conclusion The combination of intrathecal midazolam with epidural methylprednisolone resulted in prolonged duration of analgesia in patients with post herpetic neuralgia of lumbosacral dermatomes due to the complementary anti nociceptive action of intrathecal midazolam with epidural methylprednisolone on spinal nerve roots. Limitations The dose-response relationship of intrathecal midazolam was not evaluated in our study, so further study should be conducted with different doses of intrathecal midazolam for management of PHN.

Efficacy of intrathecal midazolam with or without epidural methylprednisolone for management of post-herpetic neuralgia involving lumbosacral dermatomes.

Background Chronic nononcological perineal pain has been effectively managed by ganglion Impar block. Chemical neurolysis, cryoablation, and radiofrequency ablation have been the accepted methods of blockade. Recently, pulsed radiofrequency, a novel variant of conventional radiofrequency, has been used for this purpose. Study design This was a prospective, randomized, double-blind study. Setting Two different interventional pain management centers in India. Objective To compare the efficacy of conventional radiofrequency and pulsed radiofrequency for gangliom Impar block. Methods The patients were randomly allocated to one of two groups. In the conventional radiofrequency (CRF) group (N = 34), conventional radiofrequency ablation was done, and in the PRF pulsed radiofrequency (PRF) group (N = 31), pulsed radiofrequency ablation was done. After informed and written consent, fluoroscopy-guided ganglion Impar block was performed through the first intracoccygeal approach. The extent of pain relief was assessed by visual analog scale (VAS) at 24 hours, and at the first, third, and sixth weeks following the intervention. A questionnaire to evaluate subjective patient satisfaction was also used at each follow-up visit. Results In the CRF group, the mean VAS score decreased significantly from the baseline value at each follow-up visit. But in the PRF group, this decrease was insignificant except at 24-hour follow-up. Intergroup comparison also showed significantly better pain relief in the CRF group as compared with the PRF group. At the end of follow-up, 28 patients (82%) in the CRF group and four patients (13%) in the PRF group had excellent results, as assessed by the subjective patient satisfaction questionnaire. There was no complication in any patient of either study group, except for short-lived infection at the site of skin puncture in a few. Conclusion Ganglion Impar block by conventional radiofrequency provided a significantly better quality of pain relief with no major side effects in patients with chronic nononcological perineal pain as compared with pulsed radiofrequency. Limitations The short-term follow-up period of only six weeks was a major drawback associated with this study.

Conventional Radiofrequency Thermocoagulation vs Pulsed Radiofrequency Neuromodulation of Ganglion Impar in Chronic Perineal Pain of Nononcological Origin

Thiopental (TPL) is a commonly used barbiturate anesthetic. Its binding with human serum albumin (HSA) was studied to explore the anesthetic-induced protein dysfunction. The basic binding interaction was studied by UV-absorption and fluorescence spectroscopy. An increase in the binding affinity (K) and in the number of binding sites (n) with the increasing albumin concentration was observed. The interaction was conformation-dependent and the highest for the F isomer of HSA, which implicates its slow elimination. The mode of binding was characterized using various thermodynamic parameters. Domain II of HSA was found to possess a high affinity binding site for TPL. The effect of micro-metal ions on the binding affinity was also investigated. The molecular distance, r, between donor (HSA) and acceptor (TPL) was estimated by fluorescence resonance energy transfer (FRET). Correlation between the stability of the TPL-N and TPL-F complexes and drug distribution is discussed. The structural changes in the protein investigated by circular dichroism (CD) and Fourier transform infrared (FT-IR) spectroscopy reflect perturbation of the albumin molecule and provide an explanation for the heterogeneity of action of this anesthetic.

/pdf/interaction-of-anesthetic-supplement-thiopental-with-human-4pjra6z1cd.pdf

Hammad Usmani

Papers

A Study of the Use of Laryngeal Mask Airway (LMA) in Children and its Comparison with Endotracheal Intubation

Efficacy of intrathecal midazolam with or without epidural methylprednisolone for management of post-herpetic neuralgia involving lumbosacral dermatomes.

Conventional Radiofrequency Thermocoagulation vs Pulsed Radiofrequency Neuromodulation of Ganglion Impar in Chronic Perineal Pain of Nononcological Origin

Interaction of anesthetic supplement thiopental with human serum albumin.

Acute pain services in flail chest-a prospective randomized trial of epidural versus parenteral analgesia in mechanically ventilated ICU patients