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      Skin Matters: A Review of Topical Treatments for Chronic Pain. Part One: Skin Physiology and Delivery Systems

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          Abstract

          Chronic pain is a complex disorder with multiple etiologies for which the pathologic mechanisms are still largely unknown, making effective treatment a difficult clinical task. Achieving pain relief along with improved function and quality of life is the primary goal of pain clinicians; however, most patients and healthcare professionals consider 30% pain improvement to be clinically significant—a success level that would be unacceptable in other areas of medicine. Furthermore, patients with chronic pain frequently have multiple comorbidities, including depression and sleep apnea, and most have seen several physicians prior to being seen by a pain specialist, have more than three specific pain generators, and are taking multiple medications. The addition of further oral medications to control pain increases the risk of drug–drug interactions and side effects. However, topical analgesics have the advantage of local application with limited systemic levels of drug. Topical therapies benefit from reduced side effects, lower risk of drug–drug interactions, better patient acceptability/compliance, and improved tolerability. This two-part paper is a review of topical analgesics and their potential role in the treatment of chronic pain.

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          Most cited references61

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          Cannabis in painful HIV-associated sensory neuropathy: a randomized placebo-controlled trial.

          To determine the effect of smoked cannabis on the neuropathic pain of HIV-associated sensory neuropathy and an experimental pain model. Prospective randomized placebo-controlled trial conducted in the inpatient General Clinical Research Center between May 2003 and May 2005 involving adults with painful HIV-associated sensory neuropathy. Patients were randomly assigned to smoke either cannabis (3.56% tetrahydrocannabinol) or identical placebo cigarettes with the cannabinoids extracted three times daily for 5 days. Primary outcome measures included ratings of chronic pain and the percentage achieving >30% reduction in pain intensity. Acute analgesic and anti-hyperalgesic effects of smoked cannabis were assessed using a cutaneous heat stimulation procedure and the heat/capsaicin sensitization model. Fifty patients completed the entire trial. Smoked cannabis reduced daily pain by 34% (median reduction; IQR = -71, -16) vs 17% (IQR = -29, 8) with placebo (p = 0.03). Greater than 30% reduction in pain was reported by 52% in the cannabis group and by 24% in the placebo group (p = 0.04). The first cannabis cigarette reduced chronic pain by a median of 72% vs 15% with placebo (p < 0.001). Cannabis reduced experimentally induced hyperalgesia to both brush and von Frey hair stimuli (p < or = 0.05) but appeared to have little effect on the painfulness of noxious heat stimulation. No serious adverse events were reported. Smoked cannabis was well tolerated and effectively relieved chronic neuropathic pain from HIV-associated sensory neuropathy. The findings are comparable to oral drugs used for chronic neuropathic pain.
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            Spontaneous pain, both neuropathic and inflammatory, is related to frequency of spontaneous firing in intact C-fiber nociceptors.

            Spontaneous pain, a poorly understood aspect of human neuropathic pain, is indicated in animals by spontaneous foot lifting (SFL). To determine whether SFL is caused by spontaneous firing in nociceptive neurons, we studied the following groups of rats: (1) untreated; (2) spinal nerve axotomy (SNA), L5 SNA 1 week earlier; (3) mSNA (modified SNA), SNA plus loose ligation of the adjacent L4 spinal nerve with inflammation-inducing chromic gut; and (4) CFA (complete Freund's adjuvant), intradermal complete Freund's adjuvant-induced hindlimb inflammation 1 and 4 d earlier. In all groups, recordings of SFL and of spontaneous activity (SA) in ipsilateral dorsal root ganglion (DRG) neurons (intracellularly) were made. Evoked pain behaviors were measured in nerve injury (SNA/mSNA) groups. Percentages of nociceptive-type C-fiber neurons (C-nociceptors) with SA increased in intact L4 but not axotomized L5 DRGs in SNA and mSNA (to 35%), and in L4/L5 DRGs 1-4 d after CFA (to 38-25%). SFL occurred in mSNA but not SNA rats. It was not correlated with mechanical allodynia, extent of L4 fiber damage [ATF3 (activation transcription factor 3) immunostaining], or percentage of L4 C-nociceptors with SA. However, L4 C-nociceptors with SA fired faster after mSNA (1.8 Hz) than SNA (0.02 Hz); estimated L4 total firing rates were approximately 5.0 and approximately 0.6 kHz, respectively. Similarly, after CFA, faster L4 C-nociceptor SA after 1 d was associated with SFL, whereas slower SA after 4 d was not. Thus, inflammation causes L4 C-nociceptor SA and SFL. Overall, SFL was related to SA rate in intact C-nociceptors. Both L5 degeneration and chromic gut cause inflammation. Therefore, both SA and SFL/spontaneous pain after nerve injury (mSNA) may result from cumulative neuroinflammation.
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              Cutaneous innervation in sensory neuropathies: evaluation by skin biopsy.

              To use punch skin biopsies to evaluate the loss of intra-epidermal nerve fibers in sensory neuropathies. Previous assessments of epidermal nerve fibers have been constrained by relatively insensitive staining techniques and variability in quantification. Punch skin biopsies were performed on the heel and leg of HIV-seronegative controls, HIV-seropositive individuals without neuropathy, and patients with sensory neuropathies, including HIV-seronegative and HIV-positive individuals. After formalin fixation, 50-microns free-floating sections were stained with a monoclonal antibody to neuron-specific ubiquitin hydrolase, PGP9.5. The number of intraepidermal fibers/mm in at least three sections from each patient was counted by one observer blinded to site and clinical status. Dermal and epidermal nerve fibers were readily identified and quantified. The immunostaining technique reliably demonstrated a dermal plexus of myelinated and unmyelinated fibers parallel to the surface of the skin. In the epidermis, unmyelinated fibers ascended vertically between the keratinocytes to reach the stratum corneum. The number of intra-epidermal fibers/mm in the distal leg (mean +/- SEM) was 17.84 +/- 3.03 in seven HIV-seronegative controls. Epidermal fiber number was significantly reduced (p = 0.01) in five HIV-infected patients with sensory neuropathies associated with didanosine or zalcitabine therapy (1.07 +/- 0.40) and in eight HIV-seronegative patients with sensory neuropathies (3.1 +/- 3.1). Four of five neurologically normal HIV-seropositive subjects had reduced numbers of epidermal fibers, suggesting a subclinical neuropathy. Serial biopsies in one individual demonstrated the evolution of degenerating epidermal fibers after development of zalcitabine-induced sensory neuropathy. Skin biopsies stained with the sensitive panaxonal marker anti-PGP9.5 demonstrated significant reduction in intraepidermal fibers in sensory neuropathies. This simple and repeatable technique is a reliable method for quantitation of small cutaneous sensory fibers. In addition, skin biopsies may be useful in assessing the course and spatial distribution of involvement in peripheral nerve disease.
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                Author and article information

                Contributors
                johnpeppin@msn.com
                Journal
                Pain Ther
                Pain Ther
                Pain and Therapy
                Springer Healthcare (Cheshire )
                2193-8237
                2193-651X
                28 January 2015
                28 January 2015
                June 2015
                : 4
                : 1
                : 17-32
                Affiliations
                [ ]Center for Bioethics Pain Management and Medicine, St. Louis, MO USA
                [ ]Mallinckrodt Pharmaceuticals, Hazelwood, MO USA
                [ ]Center for Neuropharmacology and Neuroscience, Albany Medical College, Albany, NY USA
                [ ]Department of Neurology, Albany Medical College, Albany, NY USA
                [ ]Intensive Care and Pain Medicine, Wilhelminenspital der Stadt Wien and Vienna Human Pain Research Group, Vienna, Austria
                [ ]Pain Medicine and Medical Biotechnologies, Postgraduate School of Anesthesia, Campus Bio-Medico University of Rome, Rome, Italy
                [ ]Pain Management and Medical Mentoring at New Medical Home for Chronic Pain, NY, USA
                [ ]Integrated Tissue Dynamics LLC, Rensselaer, NY USA
                [ ]Department of Biomedical Sciences, University at Albany, Rensselaer, NY USA
                [ ]Division of Pain Medicine, Department of Anesthesiology, University of California, San Diego, CA USA
                Article
                31
                10.1007/s40122-015-0031-0
                4470967
                25627665
                06c282a2-3850-47bf-8d24-7eeb687d1cb8
                © The Author(s) 2015
                History
                : 9 July 2013
                Categories
                Review
                Custom metadata
                © Springer Healthcare 2015

                chronic pain,neuropathic pain,rational topical polypharmacy,skin nociception,topical analgesics

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