COMPOUNDING PHARMACY SOLUTIONS PRESCRIPTION COMPOUNDING FOR PAIN MANAGEMENT

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1 JUNE 2012 COMPOUNDING PHARMACY SOLUTIONS PRESCRIPTION COMPOUNDING COM We customize individual prescriptions for the specific needs of our patients. INSIDE THIS ISSUE: Acute Pain 2 Neuropathic Pain 3 PRESCRIPTION COMPOUNDING FOR PAIN MANAGEMENT Complex Regional Pain Syndrome Beverly Hill Street Suite 201 Houston, TX Phone: (713) Fax: (713) Web:

2 Page 2 ACUTE PAIN The following clinical paper suggests that a combination of paracetamol and an NSAID may offer superior analgesia compared with either drug alone - Combining paracetamol (acetaminophen) with nonsteroidal anti-inflammatory drugs: a qualitative systematic review of analgesic efficacy for acute postoperative pain (Anesth Analg Apr;110(4):1170-9). BACKGROUND: There has been a trend over recent years for combining a nonsteroidal anti-inflammatory drug (NSAID) with paracetamol (acetaminophen) for pain management. However, therapeutic superiority of the combination of paracetamol and an NSAID over either drug alone remains controversial. We evaluated the efficacy of the combination of paracetamol and an NSAID versus either drug alone in various acute pain models. METHODS: A systematic literature search of Medline, Embase, Cumulative Index to Nursing and Allied Health Literature, and Pub- Med covering the period from January 1988 to June 2009 was performed to identify randomized controlled trials in humans that specifically compared combinations of paracetamol with various NSAIDs versus at least 1 of these constituent drugs. Identified studies were stratified into 2 groups: paracetamol/nsaid combinations versus paracetamol or NSAIDs. We analyzed pain intensity scores and supplemental analgesic requirements as primary outcome measures. In addition, each study was graded for quality using a validated scale. RESULTS: Twenty-one human studies enrolling 1909 patients were analyzed. The NSAIDs used were ibuprofen (n = 6), diclofenac (n = 8), ketoprofen (n = 3), ketorolac (n = 1), aspirin (n = 1), tenoxicam (n = 1), and rofecoxib (n = 1). The combination of paracetamol and NSAID was more effective than paracetamol or NSAID alone in 85% and 64% of relevant studies, respectively. The pain intensity and analgesic supplementation was 35.0% +/- 10.9% and 38.8% +/- 13.1% lesser, respectively, in the positive studies for the combination versus paracetamol group, and 37.7% +/- 26.6% and 31.3% +/- 13.4% lesser, respectively, in the positive studies for the combination versus the NSAID group. No statistical difference in median quality scores was found between experimental groups. CONCLUSION: Current evidence suggests that a combination of paracetamol and an NSAID may offer superior analgesia compared with either drug alone. PMID: Acetaminophen 25% / Ketoprofen 10% Transdermal Cream 120gm Apply to affected area TID The following review states that the addition of an NSAID to paracetamol may confer additional analgesic efficacy compared with paracetamol alone - Comparative effect of paracetamol, NSAIDs or their combination in postoperative pain management: a qualitative review (Br J Anaesth Feb;88(2): ). BACKGROUND: Quantitative reviews of postoperative pain management have demonstrated that the number of patients needed to treat for one patient to achieve at least 50% pain relief (NNT) is 2.7 for ibuprofen (400 mg) and 4.6 for paracetamol (1000 mg), both compared with placebo. However, direct comparisons between paracetamol and non-steroidal anti-inflammatory drugs (NSAIDs) have not been extensively reviewed. The aims of this review are (i) to compare the analgesic and adverse effects of paracetamol with those of other NSAIDs in postoperative pain, (ii) to compare the effects of combined paracetamol and NSAID with those of either drug alone, and (iii) to discuss whether the adverse effects of NSAIDs in short-term use are justified by their analgesic effects, compared with paracetamol. METHODS: Medline (1966 to January 2001) and the Cochrane Library (January 2001) were used to perform a systematic, qualitative review of postoperative pain studies comparing paracetamol (minimum 1000 mg) with NSAID in a double-blind, randomized manner. A quantitative review was not performed as too many studies of high scientific standard (27 out of 41 valid studies, including all major surgery studies) would have been excluded. RESULTS: NSAIDs were clearly more effective in dental surgery, whereas the efficacy of NSAIDs and paracetamol seemed without substantial differences in major and orthopaedic surgery, although firm conclusions could not be made because the number of studies was limited. The addition of an NSAID to paracetamol may confer additional analgesic efficacy compared with paracetamol alone, and the limited data available also suggest that paracetamol may enhance analgesia when added to an NSAID, compared with NSAIDs alone. CONCLUSION: Paracetamol is a viable alternative to the NSAIDs, especially because of the low incidence of adverse effects, and should be the preferred choice in high-risk patients. It may be appropriate to combine paracetamol with NSAIDs, but future studies are required, especially after major surgery, with specific focus on a potential increase in side-effects from their combined use. PMID: We have the ability to compound acetaminophen (paracetamol) together with ketoprofen into a transdermal cream that can be applied directly to the site of pain. This form of delivery may be useful for those patients who cannot take these medications orally.

3 Page 3 NEUROPATHIC PAIN The following report indicates that dextromethorphan has an analgesic effect in patients with neuropathic pain - Analgesic effect of dextromethorphan in neuropathic pain (Acta Anaesthesiol Scand Mar;48(3):328-36). BACKGROUND: Dextromethorphan, a clinically available N- methyl-d-aspartic acid (NMDA) receptor antagonist, has an analgesic effect in patients with diabetic neuropathy. The aim of this study was to evaluate the analgesic and adverse effects of a single high dose of dextromethorphan on spontaneous pain in patients suffering long-term neuropathic pain of traumatic origin. METHODS: Fifteen patients with post-traumatic neuropathic pain participated in this placebo-controlled, double-blind, randomized crossover study. On two separate occasions, the participants received 270 mg of dextromethorphan hydrobromide or placebo. Pain intensity, adverse effects and serum concentrations of dextromethorphan and metabolites were registered. RESULTS: Dextromethorphan had a statistically significant analgesic effect compared with placebo, but the effect varied markedly among the patients. Light-headedness was the most important adverse effect reported. Extensive metabolizers of dextromethorphan had an apparently better analgesic effect than poor metabolizers. CONCLUSION: This report indicates that a single high dose of dextromethorphan has an analgesic effect in patients with neuropathic pain of traumatic origin. The main metabolite dextrorphan seems to be important for the analgesic effect. At the relatively high dose studied, the clinical usefulness of dextromethorphan is limited to that portion of the patient population experiencing analgesia without an unacceptable level of adverse effects. PMID: With our state of the art compounding lab and pharmaceutical experience, we have the ability to compound dextromethorphan as a transdermal gel that can be applied directly to the site of pain. Dextromethorphan 10% Transdermal Gel 90ml Apply to affected area(s) BID

4 Page 4 COMPLEX REGIONAL PAIN SYNDROME The following clinical trial shows promise for the use of topical ketamine in CRPS - Reduction of allodynia in patients with complex regional pain syndrome: A double-blind placebo-controlled trial of topical ketamine (Pain Aug 22). ABSTRACT: A double-blind placebo-controlled crossover trial was used to determine the effects of topical ketamine, an N- methyl-d-aspartate (NMDA) receptor antagonist, on the sensory disturbances in 20 patients with complex regional pain syndrome (CRPS). On two occasions separated by at least one week, sensory tests to light touch, pressure, punctate stimulation, light brushing and thermal stimuli were performed in the symptomatic and contralateral limb and on each side of the forehead before and 30min after 10% ketamine cream was applied to the symptomatic or healthy limb. Venous blood for the plasma estimations of ketamine and norketamine was obtained 1h after application of the creams. Ketamine applied to the symptomatic limb inhibited allodynia to light brushing and hyperalgesia to punctate stimulation. Systemic effects of the ketamine are unlikely to account for this as the plasma levels were below detectable limits. As touch thresholds were unchanged, NMDA receptors may contribute to the sensory disturbances in CRPS via actions at cutaneous nociceptors. Allodynia and hyperalgesia were detected in the ipsilateral forehead to a range of stimuli (brushing, pressure, punctate stimulation, cold, heat, and warmth). In several patients, ketamine treatment of the symptomatic limb inhibited allodynia to brushing the ipsilateral forehead, suggesting that the mechanism that mediates allodynia in the symptomatic limb contributed to allodynia at more remote sites. The present study shows promise for the use of topical ketamine as opposed to parenteral and oral forms which often result in undesirable side effects. PMID: The following study found that gabapentin had a mild effect on pain in CRPS I - Randomised controlled trial of gabapentin in Complex Regional Pain Syndrome type 1 (BMC Neurol Sep 29;4:13). BACKGROUND: Complex Regional Pain Syndrome type one (CRPS I) or formerly Reflex Sympathetic Dystrophy (RSD) is a disabling syndrome, in which a painful limb is accompanied by varying symptoms. Neuropathic pain is a prominent feature of CRPS I, and is often refractory to treatment. Since gabapentin is an anticonvulsant with a proven analgesic effect in various neuropathic pain syndromes, we sought to study the efficacy of the anticonvulsant gabapentin as treatment for pain in patients with CRPS I. METHODS: We did a randomized double blind placebo controlled crossover study with two three-weeks treatment periods with gabapentin and placebo separated by a two-weeks washout period. Patients started at random with gabapentin or placebo, which was administered in identical capsules three times daily. We included 58 patients with CRPS type 1. RESULTS: Patients reported significant pain relief in favor of gabapentin in the first period. Therapy effect in the second period was less; finally resulting in no significant effect combining results of both periods. The CRPS patients had sensory deficits at baseline. We found that this sensory deficit was significantly reversed in gabapentin users in comparison to placebo users. CONCLUSIONS: Gabapentin had a mild effect on pain in CRPS I. It significantly reduced the sensory deficit in the affected limb. A subpopulation of CRPS patients may benefit from gabapentin. PMID: With our state of the art compounding lab and pharmaceutical knowledge and experience, we can compound ketamine and gabapentin together into one transdermal cream. Ketamine 10% / Gabapentin 6% Transdermal Cream 90gm Apply sparingly TID PRN

5 Prescriber Name Prescriber Address City State Zip Phone Fax Date Patient Name DOB Address City/State/Zip Phone Patient will pick up at pharmacy Please ship to patient Acute Pain All topical compound %s are per 1 ml or 1 gm unless otherwise noted [ ] Acetaminophen 25% / Ketoprofen 10% Transdermal Cream Quantity 120gm Neuropathic Pain Directions: Apply to affected area TID [ ] Dextromethorphan 10% Transdermal Gel Quantity 90ml Complex Regional Pain Syndrome Directions: Apply to affected area(s) BID [ ] Ketamine 10% / Gabapentin 6% Transdermal Cream Quantity 90gm Directions: Apply sparingly TID PRN Directions Prescriber s Signature Refills: NR 6105 Beverly Hill Street Suite 201 Houston, TX Phone: (713) Fax: (713)