Pain management is essential because even when the underlying disease process is stable, uncontrolled pain prevents patients from working productively, enjoying recreation, or taking pleasure in their usual roles in the family and society. Chronic pain may have a myriad of causes and perpetuating factors, and therefore can be much more difficult to manage than acute pain, requiring a multidisciplinary approach and customized treatment protocols to meet the specific needs of each patient.
Optimal treatment may involve the use of medications that possess pain-relieving properties, including some antidepressants, anticonvulsants, antiarrhythmics, anesthetics, antiviral agents, and NMDA (N-methyl-D-aspartate) antagonists. NMDA-receptor antagonists, such as dextromethorphan and ketamine, can block pain transmission in dorsal horn spinal neurons, reduce nociception, and decrease tolerance to and the need for opioid analgesics. [Anesth Analg 2001 Mar;92(3):739-44] By combining various agents which utilize different mechanisms to alter the sensation of pain, physicians have found that smaller concentrations of each medication can be used.
Topical and transdermal creams and gels can be formulated to provide high local concentrations at the site of application (e.g., NSAIDs for joint pain), for trigger point application (e.g., combinations of medications for neuropathic pain), or in a base that will allow systemic absorption. Side effects associated with oral administration can often be avoided when medications are used topically. Studies suggest that there are no great restrictions on the type of drug that can be incorporated into a properly compounded transdermal gel. When medications are administered transdermally, they are not absorbed through the gastrointestinal system and do not undergo first-pass hepatic metabolism.
We work together with patient and practitioner to solve problems by customizing medications that meet the specific needs of each individual. Please contact our compounding pharmacist to discuss the dosage form, strength, and medication or combination that is most appropriate for your patient.
Topical and transdermal “pain formulations have wide popularity among health care providers and patients when they are used, but there are indications that not all providers are familiar with how to best prescribe them and use them. A study of 120 pain clinicians revealed that only 27% reported frequently prescribing compounded topical pain medications, with a success rate of 47%.” Topical and transdermal preparations are often preferred to oral medications due to decreased systemic side effects and the avoidance of first-pass hepatic metabolism. Dosage forms include creams, ointments, and gels; medication sticks; solutions, and sprays.
Topics in Pain Management: February 2016 – Volume 31 – Issue 7 – p 1–8
Use of Topical Pain Medications in the Treatment of Various Pain Syndromes
Click here to access the PubMed abstract of this article.
How Compounding and Transdermal Medications May Help with the Opioid Crisis
Traditionally, opioid analgesics were reserved for a few select conditions, such as terminal illness and surgery, but more recently opioids have been readily prescribed for multiple conditions. Transdermal compounded medications are patient-specific and customizable to include different types of drugs, in various dosage strengths, that can be delivered simultaneously in one application. Due to the different origins and types of pain, treatments may be most beneficial when multiple classes of drugs with various mechanisms of action are included. In addition, combination drug therapy may include nontraditional pain management options, and has the ability to maximize therapeutic effects of medications through additive or synergistic properties, often allowing the dosage of individual drugs to be decreased. Many of the challenges faced when using oral opioid therapy may be overcome by using transdermal drug delivery since this route of administration reduces adverse effects, increases patient compliance, and limits exposure to potentially abusive drugs.
J Opioid Manag. 2018 Jan/Feb;14(1):17-22.
The role of transdermal compounding in opioid safety.
Click here to access the PubMed abstract of this article.
Topical Prazosin Attenuates Sensitivity to Tactile Stimuli in Complex Regional Pain Syndrome
In this study, both in patients and controls, topical application of prazosin 1% cream increased sensitivity to skin cooling but reduced hyperalgesia to sharp stimulation and allodynia to brushing. Topical therapy uses smaller doses compared to oral medications, and can help to prevent systemic side-effects.
Eur J Pain. 2016 Jul;20(6):926-35.
Topical prazosin attenuates sensitivity to tactile stimuli in patients with complex regional pain syndrome.
Click here to access the PubMed abstract of this article.
Novel Anti-inflammatory Gel for Transdermal Delivery
When compounding medications, a compounding pharmacy must continually expand its armamentarium of bases, from which the most appropriate base is selected for the intended use of a compounded preparation.
The results from the in vitro study showed that the ricinoleic acid gel possessed significantly higher anti-inflammatory activity than isopropyl palmitate gel. Further testing of the formulation showed that the ricinoleic acid gel formulation significantly reduced pain and edema when compared to the isopropyl palmitate gel. In addition, the ricinoleic acid gel formulation markedly inhibited the synthesis of prostaglandin E2.
Int J Pharm. 2015 Feb 1;479(1):207-11.
Anti-inflammatory effects of a novel ricinoleic acid poloxamer gel system for transdermal delivery
Click here to access the PubMed abstract of this article.
Topical and Transdermal Drug Administration
Topical drug treatment aims at providing high concentrations of drugs at the site of application so as to avoid adverse systemic effects associated with oral administration. Smart polymers, or stimuli-responsive polymers, are able to respond to a stimulus by showing physical or chemical changes in the delivery of the drug carried by them. The thermo-responsive nature of certain gels makes them excellent candidates for the delivery of drugs at various application sites. These bases have attracted particular interest in the formulation of topical and transdermal delivery systems with regard to promoting, improving, or retarding drug permeation through the skin, bearing in mind that for topical delivery systems, accumulation in the skin with minimal permeation is desired, while for systemic delivery, the opposite behavior is preferred.
J Pharm Pharm Sci. 2012;15(4):592-605.
Pluronic® F-127 and Pluronic Lecithin Organogel (PLO): main features and their applications in topical and transdermal administration of drugs.
Click here to access the PubMed abstract of this article.
Neuropathic Pain
Topical Loperamide for Localized Neuropathic Pain
Peripheral nerve damage can result in neuronal hyperexcitability and neuropathic pain. Localized neuropathic pain is confined to a specific area not larger than a letter-size paper. Topical analgesics are increasingly popular for the treatment of localized neuropathic pain because systemic agents for managing neuropathic pain often produce undesirable and intolerable side effects. Medications commonly compounded for topical use include amitriptyline, baclofen, ketamine, and lidocaine; however, these agents do not always give the desired analgesic effect in some patients. Kopsky et al. reported for the first time a patient with chronic idiopathic axonal polyneuropathy and intractable localized neuropathic pain was treated successfully with loperamide 5% cream. After the application of loperamide 5% cream, the patient reported a complete reduction of pain within 30 minutes, lasting for 2.5 hours. Subsequently, the patient was able to reduce his daily intake of oxycodone, while using topical loperamide for pain relief. Loperamide is an opioid agonist, commonly used to treat diarrhea. As a topical formulation, it is preferable over other opioids due to its low systemic bioavailability and low risk of crossing the blood-brain barrier. Peripheral upregulation and sensitization of opioid receptors at peripheral nerve endings and perhaps at other cell populations in the epidermis might be achieved with topical loperamide.
J Pain Res. 2019 Apr 29;12:1189-1192.
Topical loperamide for the treatment of localized neuropathic pain: a case report and literature review
Click here to access the PubMed abstract of this article.
Treatment of Complex Regional Pain Syndrome (CRPS) Using Low Dose Naltrexone (LDN)
Complex Regional Pain Syndrome (CRPS), formerly known as Reflex Sympathetic Dystrophy (RSD), is a neuropathic pain syndrome that is characterized by a combination of sensory, autonomic, vasomotor, and motor dysfunctions, with pain that is out of proportion to the initial injury. Diagnoses of CRPS are often delayed because it is under-recognized. CRPS involves glial activation and central sensitization in the central nervous system. If appropriate treatments are started early enough in the progression of the disease, there is a reduced chance for the spread of regional pain, autonomic dysfunction, motor changes, and negative sensory symptoms. As CRPS progresses, it becomes refractory to sympathetic nerve blocks, conventional analgesics, anticonvulsants, and anti-depressants. Low-dose naltrexone (LDN) refers to doses approximately 50-fold lower than doses of naltrexone typically given to patients addicted to opioids. Low-dose naltrexone (LDN) is known to antagonize the Toll-like Receptor 4 (TLR4) pathway and attenuate activated microglia.
Glial attenuators such as LDN are likely to provide benefits in controlling CNS neuroinflammation that arises from peripheral nerve injury, CNS injury, or autoimmune attack on CNS targets. However, it is possible that inhibiting CNS neuroinflammation with glial attenuators might be deleterious to individuals who are immuno-compromised or have an ongoing viral or bacterial infection.
J Neuroimmune Pharmacol. 2013 Jun;8(3):470-6.
Treatment of Complex Regional Pain Syndrome (CRPS) using low dose naltrexone (LDN).
Click here to access the PubMed abstract of this article.
Topical and Intranasal Therapy for Refractory Postherpetic Neuralgia
A patient-specific, stepped approach to topical and intranasal analgesic pharmacotherapy was effective in reducing refractory postherpetic neuralgia (PHN) not responding to the current standard of care for PHN. The use of topical analgesic therapy allowed for higher concentrations of medication locally while reducing the likelihood of systemic side effects common to the drugs used. No adverse effects were noted for either topical or intranasal drug therapy. This approach resulted in clinically significant decreases in pain on the visual analog scale (VAS), with the use of intranasal ketamine 10% solution and topical gabapentin 6%, ketoprofen 10%, lidocaine 5%, and ketamine 10% cream.
Case Rep Med. 2015;2015:392874.
Topical and Intranasal Analgesic Therapy in a Woman with Refractory Postherpetic Neuralgia
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Topical Amitriptyline and Ketamine for Neuropathic Pain
Topical amitriptyline-ketamine combination is a promising agent for peripheral neuropathic pain conditions. Efficacy may depend on many factors, including the choice of vehicle, method of compounding, concentration, site of pain, and specific diseases.
Expert Rev Neurother. 2015;15(11):1249-53.
Topical amitriptyline and ketamine for the treatment of neuropathic pain.
Click here to access the PubMed abstract of this article.
Topical Clonidine for Neuropathic Pain
Clonidine is a presynaptic alpha-2-adrenergic receptor agonist used for many years to treat hypertension and other conditions, including chronic pain. Adverse events associated with systemic use of the drug have limited its application. Topical use of drugs is currently gaining interest, as it may limit adverse events without loss of analgesic efficacy. Topical clonidine formulations have been investigated recently in clinical trials.
Cochrane Database Syst Rev. 2015 Aug 31;8:CD010967.
Topical clonidine for neuropathic pain.
Click here to access the PubMed abstract of this article.
Severe Postherpetic Neuralgia Relieved by Topical Gabapentin
Herpes zoster reactivation, shingles, affects 0.2% of the population and postherpetic neuralgia (PHN) occurs in 10 -15% of patients following an episode of shingles, with the greatest risk in the elderly. A retrospective review involved 23 consecutive patients attending a tertiary complex pain clinic (University Hospital of Wales, Cardiff and Vale University Local Health Board), who were treated with topical gabapentin gel.
Multiple studies have already demonstrated the efficacy of oral gabapentin in treating chronic neuropathic pain, however, efficacy is often limited by dose-dependent toxicity. Although this patient population was small, these findings support the use of topical gabapentin in the treatment of PHN and potentially other painful neuropathy.
Br J Dermatol. 2014 Dec 18.
Severe postherpetic neuralgia and other neuropathic pain syndromes alleviated by topical gabapentin
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Topical Analgesics for Neuropathic Pain in the Elderly
Elderly patients exhibit a higher incidence of several neuropathic pain conditions than younger individuals. Systemic treatment of neuropathic pain in the elderly usually requires lower dosing, slower titration, and more monitoring (for efficacy, adverse effects) than in younger patients due to drug factors (altered pharmacokinetics and pharmacodynamics) and patient factors (comorbidities, polypharmacy, frailty). “Despite the availability of several options, treatment of neuropathic pain is not optimal, as medications provide only a partial effect and adverse effects can limit dose escalation, resulting in suboptimal dosing. An often quoted perspective is that less than 50% experience satisfactory pain relief, and side effects are common.”
Summary of perspectives on topical analgesics and relevance to the elderly:
- Topical analgesics are beneficial in a proportion of those with neuropathic pain and can produce a degree of analgesia that is comparable with that of oral agents.
- Topical analgesics are well tolerated, with adverse effects being mainly due to localized skin reactions. Low systemic levels occur following topical administration and do not contribute to systemic adverse effects or drug interactions.
- Topical analgesics may be used as alternative analgesics (when systemic analgesics are not tolerated) or as add-on analgesics when an oral agent produces a partial effect (their addition does not increase the side effect burden).
- Only a limited number of topical analgesics are currently approved, but there is interest in investigational agents that recruit several potential mechanisms of action, and additional options may become available.
- Topical analgesics have the potential to contribute to improved pain management in the elderly based on their efficacy, adverse effect profile, potential for use as add-on therapies, and potential for oral analgesic-sparing effects with ensuing reduction in adverse effects.
Drugs Aging. 2014 Dec;31(12):853-62.
Topical analgesics for neuropathic pain in the elderly: current and future prospects.
Click here to access the PubMed abstract of this article.
Eur J Pain. 2014 Apr;18(4):465-81.
Topical analgesics for neuropathic pain: preclinical exploration, clinical validation, future development.
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Amitriptyline/Ketamine for Neuropathic Pruritus and pain secondary to herpes zoster.
Neuropathic pruritus is a complication of herpes zoster which can be either acute or post-infectious when it persists more than 3 months after the rash has healed. In the study, modest control of the pruritus and pain was achieved with continued multimodal therapy and the addition of topical 2% amitriptyline/0.5% ketamine gel.
J Drugs Dermatol. 2015 Feb;14(2):115-8.
Amitriptyline/Ketamine as therapy for neuropathic pruritus and pain secondary to herpes zoster.
Click here to access the PubMed abstract of this article.
Topical therapies and combination preparations may have many advantages over systemically administered analgesics, including the ability to provide effective analgesia with reduced systemic drug levels, a factor particularly beneficial to the elderly. Fewer side effects coupled with convenient and painless administration result in improved patient acceptance and compliance, and ease of use may reduce overall treatment costs. Because they are applied directly to the target site, topical administration can provide therapeutic levels in the tissues under the area of application, with minimal serum levels. Lower systemic drug levels potentially lower the risk of organ toxicity. In addition, first-pass hepatic metabolism and other variables associated with the gastrointestinal tract are avoided. Topical therapy is a viable solution that often avoids the need for injections when oral dosing is not feasible because the patient is nauseated or unconscious. Existing commercially available treatments may have limited effectiveness and produce relatively frequent adverse effects. Patients often convey that different medications will impart distinct analgesic benefits. The presence of side effects such as insomnia, depression, anxiety, and fatigue can diminish the patient’s quality of life, and justify a change to a customized therapy. There is a growing body of evidence on the efficacy and safety of topical agents in a variety of pain disorders, including the most prevalent neuropathic pain conditions. The molecular basis for the usage of peripheral analgesics in neuropathic pain and the available clinical trial evidence for a wide variety of topical agents are reviewed in an excellent article by Oscar A. de Leon-Casasola, MD, Department of Anesthesiology and Critical Care Medicine, Roswell Park Cancer Institute, School of Medicine and Biomedical Studies, State University of New York at Buffalo. Agents “that profoundly reduce neurotransmitter release from nociceptors generating ectopic pulses, such as topical local anesthetics and anticonvulsants, may relieve neuropathic pain. Likewise, increased peripheral sensitivity mediated through the release of prostaglandin E2 and substance P at the peripheral level results in spontaneous discharges that may be inhibited by topical drugs, such as nonsteroidal anti-inflammatory drugs (NSAIDs)… Additionally, topical substance P inhibitors and ketamine can reduce the effects of substance P, while sympathetic afferent activation can be modified by the topical administration of a beta-blocker and clonidine. Topical antihistamine may decrease the release of histamine and serotonin, thereby limiting the inflammatory process and hindering vasodilation. Topical opioids can target the opioid receptors present on nociceptive fibers and mast cells. Binding of opioid receptors can inhibit the release of the calcitonin gene-related peptide (CGRP) and substance P from nerves, thereby preventing the feed-forward mechanism of pain that typically results in sensitization at the site of injury (primary hyperalgesia).” Pentoxifylline has effectively provided relief for some neuropathic conditions when applied topically. “Topical tricyclic antidepressants, such as doxepin and amitriptyline, have demonstrated efficacy in a number of neuropathic pain states.”Neuropathic pain is often resistant to opioids, so other medication classes – such as tricyclic antidepressants, anticonvulsants, and local anesthetics – are often used. Central sensitization, or pain “wind-up”, may perpetuate chronic neuropathic pain even when ongoing peripheral sensory input is absent. Wind-up is thought to cause allodynia, hyperalgesia, and hyperpathia. Receptors such as NMDA, AMPA, and M-glu have recently been identified for their role in central sensitization, and antagonists of these receptors have produced pain relief.The analgesic effect of tricyclic antidepressants is independent of their antidepressant activity and generally occurs at low doses with the onset of pain relief in one to two weeks. For example, the analgesic effect of topically applied doxepin hydrochloride in chronic human neuropathic pain was described in a randomized, double-blind, placebo-controlled study of 200 adult patients. Fewer side effects were reported compared with oral administration.
Med Clin North Am. 2007 Jan;91(1):113-24.
Adjuvant analgesics.
Click here to access the PubMed abstract of this article.
J Pain Symptom Manage. 2007 Mar; 33(3):356-64.
Transdermal Lidocaine and Ketamine for Neuropathic Pain: A Study of Effectiveness and Tolerability
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Reg Anesth Pain Med 2003 Jul-Aug;28(4):289-93
Topical amitriptyline in healthy volunteers.
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Pain Clin 2000;12(1):47-50.
No abstract available.
A phase 2b double-blind, randomized, placebo-controlled clinical trial, involving topical gel candidate ARC-4558 for adults with painful diabetic neuropathy produced effective results in relieving the pain.
Topical Gel to Treat Diabetic Neuropathy Proves Successful in Phase 2
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Dextromethorphan/Quinidine for Treatment of Diabetic Neuropathic Pain
Diabetic peri2pheral neuropathy (DPN) is a common complication of diabetes. The most frequent form, estimated to affect 50% of diabetic patients, is a distal symmetric polyneuropathy. The associated pain, which affects approximately 25% of DPN patients, can be severe and disabling.
In a 13-week, phase 3, randomized double-blind controlled trial, 379 adults with daily symmetric diabetic peripheral neuropathy (DPN) leg pain of 3 months duration received placebo, dextromethorphan/quinidine (DMQ) 45/30 mg, or DMQ 30/30 mg, administered once daily for 7 days and twice daily thereafter. The results of this study demonstrate that DMQ was more effective than placebo in the treatment of DPN pain at both dose levels studied.
Pain Med. 2012 Feb;13(2):243-54.
Efficacy and safety of dextromethorphan/quinidine at two dosage levels for diabetic neuropathic pain: a double-blind, placebo-controlled, multicenter study.
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Study subjects with moderate to severe peripheral neuropathic pain found that the use of topical 2% amitriptyline/1% ketamine cream was well tolerated and was associated with long-term reduction in perceived pain.
J Pain. 2005 Oct;6(10):644-9.
Topical amitriptyline and ketamine in neuropathic pain syndromes: an open-label study.
Click here to access the PubMed abstract of this article.
Topical Clonidine for Diabetic Neuropathy
A phase 2b double-blind, randomized, placebo-controlled clinical trial, showed that a topical clonidine 0.1% gel relieved pain in adults with painful diabetic neuropathy and no serious side effects were reported.
https://www.mdmag.com/medical-news/topical_ge_diabetic_neuropathy
Amitriptyline/Ketamine Topical Cream for Treating Post-Herpetic Neuralgia (PHN)
Combinations of synergistic drugs can be customized for the patient with chronic pain, and topical or transdermal formulations offer excellent alternatives, sometimes with fewer side effects compared to the same drugs when taken orally. A multicenter, double-blind, randomized, placebo-controlled study was conducted to evaluate the efficacy and safety of amitriptyline 4%/ketamine 2% [NP-H] and amitriptyline 2%/ketamine 1% [NP-L] topical creams versus placebo in 251 PHN patients. NP-H was numerically superior to NP-L cream and placebo and appears to be the optimal concentration for PHN treatment. Less than 5% of subjects who applied NP-H had detectable serum levels of amitriptyline or ketamine.
This study was presented at the 2007 American Pain Society Annual Meeting, Poster #787
The following article discusses the use of topical ketamine 0.5% (5 mg/ml) gel, applied as a thin film two to three times daily over the skin where pain was severe. Topical ketamine reduced pain for patients with postherpetic neuralgia with no systemic side effects.
Neurology 2003;60:1391-1392
Topical ketamine treatment of postherpetic neuralgia
No abstract available. Click here to purchase the full article online.
The following randomized, double-blind, placebo-controlled study assessed the analgesic efficacy of topical administration of 3.3% doxepin hydrochloride, 0.025% capsaicin, or a combination applied daily for 4 weeks in 200 adult patients with chronic neuropathic pain and reported that all three preparations significantly reduced overall pain.
Br J Clin Pharmacol 2000 Jun;49(6):574-9
Topical application of doxepin hydrochloride, capsaicin, and a combination of both produces analgesia in chronic human neuropathic pain: a randomized, double-blind, placebo-controlled study.
Click here to access the PubMed abstract of this article.
Migraine
Migraine Treatment using Oxytocin
A single-dose, placebo-controlled, double-blind study found intranasal oxytocin to be highly effective in the management of chronic migraine. From 2 to 4 hours, 64% of the patients who received the agent reported a reduction in pain either from “severe to mild or none,” or from “moderate to none”, compared with only 27% of patients who received a placebo.
2013 International Headache Congress. Abstract P59.
To relieve migraine sufferers from pain and reduce the occurrence of migraines, it is important for a clinician to be aware of the four phases and pathophysiology of migraines, drug classes commonly used, various therapeutic approaches, and treatment options.
Int J Pharm Compd. 2006 Sept-Oct;10(5):344-350.
Migraine: A General Approach to Prevention and Treatment.
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Migraine is associated with a widespread metabolic abnormality of mitochondrial oxidative metabolism, leading to the use of riboflavin and coenzyme Q10 as prophylactic therapy for migraine. Riboflavin has the potential of increasing mitochondrial energy efficiency, and riboflavin 400 mg daily was found to be effective for migraine prophylaxis, with decreased attack frequency, fewer headache days, and reduced severity of migraine. Riboflavin 400 mg can be compounded in a slow-release dosage form.
Headache. 2012 Oct;52 Suppl 2:81-7.
CoEnzyme Q10 and riboflavin: the mitochondrial connection.
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Vitam Horm. 2004;69:297-312.
Role of magnesium, coenzyme Q10, riboflavin, and vitamin B12 in migraine prophylaxis.
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Cephalalgia. 1994 Oct;14(5):328-9.
High-dose riboflavin as a prophylactic treatment of migraine: results of an open pilot study.
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Continuum (Minneap Minn). 2012 Aug;18(4):796-806.
Nonmedication, alternative, and complementary treatments for migraine.
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The goal of acute therapy is to abort or reduce the pain and other symptoms associated with the migraine while minimizing adverse drug effects and ultimately restoring the patient’s ability to function normally. For the acute management of migraine without aura, a double-blind, placebo-controlled trial demonstrated that in 83% of patients, a single dose of sublingual piroxicam 40 mg provided significant analgesic effect within 15 minutes of ingestion, and a further reduction in pain in the 24 hours after drug administration, with excellent tolerability.
J Assoc Physicians India. 2011 Aug;59:494-7.
Sublingual piroxicam in migraine without aura.
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Case Report: A 40 year old woman with history of hysterectomy at age 28 and recurrent migraines refractory to treatment with multiple triptans and ergotamine/caffeine suppositories was prescribed a compounded therapy of ketoprofen 12.5mg/riboflavin 100 mg/caffeine citrate 65mg capsules, with directions to take 2 capsules at onset of migraine then two capsules every 4 hours as needed. After 3 weeks, she reported that on four occasions, her migraine was relieved with only the onset dose, and on one other occasion, she required a follow-up dose. She then added progesterone cream (applied twice daily) and three months later reported that she had only two migraines in the three month period, and both were relieved with the Ketoprofen/Riboflavin/Caffeine Capsules.
Int J Pharm Compd. 2007 May-June;11(3):200.
Case Report: Ketoprofen/Riboflavin/Caffeine Capsules and Progesterone Therapy for Recurrent Migraine Pain.
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The following article concludes: A fixed combination of indomethacin 25 mg, prochlorperazine dimaleate 4 mg, and caffeine 75 mg is significantly more effective than sumatriptan in the acute treatment of migraine attacks versus sumatriptan 25 mg, both rectal suppositories.
Headache. 2003 Sep;43(8):835-44
Efficacy of a fixed combination of indomethacin, prochlorperazine, and caffeine versus sumatriptan in acute treatment of multiple migraine attacks: a multicenter, randomized, crossover trial.
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The following article concludes: Oral therapy with a combination of LAS (equivalent to 900 mg ASA) and metoclopramide 10 mg was superior to placebo with therapeutic gains of 30% and 31% for the first treated attack, and was comparable to 100 mg sumatriptan.Funct Neurol. 2000;15 Suppl 3:196-201
The effectiveness of combined oral lysine acetylsalicylate and metoclopramide (Migpriv) in the treatment of migraine attacks. Comparison with placebo and oral sumatriptan.
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NSAID Therapy
“Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used in the treatment of pain associated with a variety of indications, including arthritic conditions, but their usefulness is often limited by dose-dependent adverse events such as gastrointestinal disturbances, cardiovascular events, and renal toxicity. The risk of such effects could be reduced by the use of topical formulations, which offer the potential to deliver analgesic concentrations locally, at the site of inflammation, while minimizing systemic concentrations… Meta-analyses have confirmed the efficacy and safety of these [TOPICAL] preparations. However, it is important to recognize that pharmacokinetics [and] absorption from topical formulations can vary markedly, even between different formulations of the same drug, depending on the agent, the underlying disorder, and the site of application. It is therefore essential to consider the patient, the drug, and the drug delivery mechanism when selecting a topical NSAID preparation.”
Am J Ther. 2015 Sep-Oct;22(5):388-407
Topical Nonsteroidal Anti-Inflammatory Drugs: The Importance of Drug, Delivery, and Therapeutic Outcome.
Click here to access the PubMed abstract of this article.
Managing Osteoarthritic Pain with Topical NSAIDs
Osteoarthritis (OA) is a leading cause of pain and disability worldwide. Due to the rapid aging of the world’s population, OA of the hands, knees, and lower back is expected to be one of the major challenges to maintaining physical function and quality of life in the elderly. Topical NSAIDS are expected to be at the forefront of providing relief from osteoarthritic pain while avoiding systemic exposure – an important consideration in a patient population with frequent co-morbidities and age-related decline in renal and hepatic function.
The best available evidence indicates that topical NSAIDs have a moderate effect on the relief of osteoarthritic pain, comparable to that of oral NSAIDs but with a better risk-to-benefit ratio. International clinical practice guidelines recommend topical NSAIDs on par with or ahead of oral NSAIDs for pain management in patients with knee and hand osteoarthritis, and as the first-line choice in persons aged ≥ 75 years.
Primary symptoms of OA include joint pain, stiffness, and movement limitation with occasional effusion and variable degrees of local inflammation. Treatment goals are to manage pain, reduce inflammation and maintain joint function. NSAIDs are central to the pharmacological management of OA. However, frequent or prolonged use of oral NSAIDs in chronic conditions such as OA raises tolerability and safety concerns, especially in more vulnerable populations such as the elderly and those with predisposing co-morbidities including high cardiovascular risk, type 2 diabetes and renal dysfunction. Oral NSAIDs are associated with age- and dose-related risks of gastrointestinal, cardiovascular, renal and hepatic adverse events.
Topical NSAIDs operate under the same mechanism of action as oral NSAIDs but with localized absorption and effect. Topical NSAIDs provide analgesic concentrations at the site of pain/inflammation, while avoiding systemic distribution of drug at physiologically active levels.
Systematic reviews and meta-analyses reporting on the efficacy and safety of topical NSAIDs found that most evidence exists for topical ketoprofen and diclofenac. “Topical NSAIDs are effective and should be recommended as a first-line intervention for mild to moderate pain associated with musculoskeletal disorders.”
The National Institute for Health and Clinical Excellence (2014) recommends that for hand and knee OA, topical NSAIDs should be considered for pain relief ahead of oral NSAIDs, COX-2 inhibitors, or opioids. The Osteoarthritis Research Society International reported topical NSAIDs are appropriate to treat knee OA in patients with or without co-morbidities.
In the treatment of acute musculoskeletal pain (e.g., sprains, strains, and overuse injuries) in adults, topical NSAIDs were found to provide significantly higher rates of clinical success (more patients with ≥50% pain reduction) than topical placebo during short-term use (less than 7 days), with an efficacy comparable to that of oral NSAIDs. Topical NSAIDs were well tolerated during short-term use.
The balance of lipophilic and hydrophilic components in gel-based formulations allows for faster diffusion across the skin and greater absorption in local tissues when compared with ointments and creams. Gels have better cosmetic acceptability since they spread and vanish more readily and are devoid of fatty components that leave a greasy residue. When assessed for ease of application, rate of penetration, after-feel, and scent, ketoprofen gel scored higher than diclofenac and piroxicam.
Pain Manag. (2018) 8(2), 115–128
Consensus recommendations for managing osteoarthritic pain with topical NSAIDs in Asia-Pacific
Click here to access the PubMed abstract of this article.
Topical Therapies in the Management of Chronic Pain
Chronic pain, whether localized or generalized, is a widespread, often debilitating condition affecting > 25% of adults. Topical therapies offer advantages over systemically administered medications, including the requirement of a lower total systemic daily dose for patients to achieve pain relief, site-specific drug delivery, and avoidance of first-pass metabolism, major drug interactions, and systemic side effects. Topical NSAIDs have been shown to have a lower incidence of gastrointestinal complaints than oral formulations. In patients with neuropathic pain, topical formulations have been shown to be useful in the treatment of postherpetic neuralgia and diabetic peripheral neuropathic pain, and in relieving patient pain due to complex regional pain syndrome. Data suggest that topical therapies may offer a well-tolerated alternative to systemic therapies in the treatment of patients with chronic, localized musculoskeletal and neuropathic pain.
Postgrad Med. 2013 Jul;125(4 Suppl 1):25-33.
Topical therapies in the management of chronic pain.
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Comparison of Analgesic Activities of Compounded Topical Creams and Voltaren® Gel in Chronic Non-cancer Pain
Pharmacologic treatment of chronic pain is challenging. Oral therapy may require multiple medications; each has side effects, dose limitations, and limited efficacy. Compounded topical formulations have evolved as potential treatment options. The objective of a study was to evaluate the efficacy of 2 compounded topical creams, “Cream I” and “Cream II,” in patients with chronic extremity, joint, musculoskeletal, neuropathic, or other chronic pain conditions and compare their efficacy with Voltaren® gel. The primary efficacy outcome was the change in visual numeric pain intensity score from pretreatment to posttreatment. Cream I contained flurbiprofen 20%, tramadol 5%, clonidine 0.2%, cyclobenzaprine 4%, and bupivacaine 3%. Cream II contained flurbiprofen 20%, baclofen 2%, clonidine 0.2%, gabapentin 10%, and lidocaine 5%. The Voltaren® gel contained 1% diclofenac sodium. A total of 2177 patients were evaluated, 826 males and 1351 females. During their medical treatment, 1141 patients received Cream I, 527 patients received Cream II, and 509 patients received Voltaren® gel. After treatment, the pain intensity score decreased by 37% with Cream I, by 35% with Cream II, and by 19% with Voltaren® gel. Cream I and Cream II did not differ significantly in efficacy, and both were significantly more effective than Voltaren® gel.
Am J Ther. 2015 Sep-Oct;22(5):342-9.
Retrospective Evaluation on the Analgesic Activities of 2 Compounded Topical Creams and Voltaren® Gel in Chronic Noncancer Pain.
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To avoid the risks of COX-2 inhibitors, our pharmacy can compound topically applied NSAIDs such as ibuprofen and ketoprofen. Topical NSAIDs have a safety profile which is superior to oral formulations. Topical NSAID administration offers the advantage of local, enhanced delivery to painful sites with a reduced incidence of systemic adverse effects.
Topical preparations can be customized to contain a combination of medications to meet the specific needs of each patient.
This study concluded that topical NSAIDs, when used for the treatment of pain resulting from strains, sprains or sports or overuse-type injuries, can provide good levels of pain relief without the systemic adverse events associated with oral NSAIDs.
Cochrane Database Syst Rev. 2010 Jun 16; 6: CD007402.
Topical NSAIDs for acute pain in adults.
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“Topical non-steroidal anti-inflammatory drugs have a lower incidence of gastrointestinal adverse effects than the same drugs when they are taken orally. The low incidence of systemic adverse effects for topical NSAIDs probably results from the much lower plasma concentration from similar doses applied topically to those administered orally. Topical application of ibuprofen resulted in measurable tissue concentrations in deep tissue compartments, more than enough to inhibit inflammatory enzymes.”
BMJ. 1995 Jul 1;311(6996):22-6
Topical non-steroidal anti-inflammatory drugs and admission to hospital for upper gastrointestinal bleeding and perforation: a record linkage case-control study.
Free full text article available at bmj.com:
//bmj.bmjjournals.com/cgi/content/full/311/6996/22
This study concludes that topical NSAIDs have not been associated with renal failure.
QJM. 1995 Aug;88(8):551-7
Non-steroidal anti-inflammatory drugs and hospitalization for acute renal failure.
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The following article concludes: “Topical non-steroidal anti-inflammatory drugs are effective in relieving pain in acute and chronic conditions.”
BMJ. 1998 Jan 31;316(7128):333-8
Quantitative systematic review of topically applied non-steroidal anti-inflammatory drugs.
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“The systemic concentrations of ketoprofen have also been found to be 100 fold lower compared to tissue concentrations below the application site in patients undergoing knee joint surgery. Topically applied ketoprofen thus provides high local concentration below the site of application but lower systemic exposure.”
Pharm Res. 1996 Jan;13(1):168-72
Percutaneous absorption of ketoprofen from different anatomical sites in man.
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Sever disease is the most common cause of heel pain in pre-pubertal children. This inflammatory condition is a result of minor repetitive trauma and typically occurs during a growth spurt or at the beginning of a new sports season. A case report described the use of topical ketoprofen 10% gel to relieve pain and inflammation.
Phys Ther. 2006 Mar;86(3):424-33
Ketoprofen gel as an adjunct to physical therapist management of a child with Sever disease.
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Topical Anesthetics
This study suggests that due to its prompt analgesia, lack of systemic side effects, and convenience, xylocaine pump spray provides a significant improvement in posttraumatic peripheral neuropathy.
Anesth Analg. 2009 Mar;108(3):987-91.
The analgesic effect of a metered-dose 8% lidocaine pump spray in posttraumatic peripheral neuropathy: a pilot study.
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A double-blind placebo-controlled crossover trial showed that in patients with Complex Regional Pain Syndrome (CRPS; also known as Reflex Sympathetic Dystrophy), topical application of ketamine 10% cream caused a reduction in allodynia, a most unpleasant aspect of this condition. This study shows promise for the use of topical ketamine as opposed to parenteral and oral forms which often result in undesirable side effects.
Pain. 2009 Nov;146(1-2):18-25.
Reduction of allodynia in patients with complex regional pain syndrome: A double-blind placebo-controlled trial of topical ketamine.
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“Lidocaine lollipop is a promising form of local oropharyngeal anesthesia for EGD. Its use resulted in sparing the use of intravenous sedation. It is well tolerated and safe and may be particularly important in the elderly, patients with comorbidities, and office-based endoscopy. “
Gastrointest Endosc. 2007 Oct;66(4):786-93.
Lidocaine lollipop as single-agent anesthesia in upper GI endoscopy.
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Topical piroxicam 0.5% gel was associated with fewer inflammatory side effects than was EMLA cream, because of its anti-inflammatory effect after the procedure.
Lasers Med Sci. 2008 Aug 21. [Epub ahead of print]
A clinical comparison of topical piroxicam and EMLA cream for pain relief and inflammation in laser hair removal.
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The following article concludes: “LAT gel (4% lidocaine, 1:2000 adrenaline, 0.5% tetracaine) worked as well as TAC gel (0.5% tetracaine, 1:2000 adrenaline, 11.8% cocaine) for topical anesthesia in facial and scalp lacerations. Considering the advantages of a noncontrolled substance and less expense, LAT gel appears to be better suited than TAC gel for topical anesthesia in laceration repair in children.”
Pediatrics 1995 Feb;95(2):255-8
Lidocaine adrenaline tetracaine gel versus tetracaine adrenaline cocaine gel for topical anesthesia in linear scalp and facial lacerations in children aged 5 to 17 years.
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The following article reported that a triple-anesthetic gel containing benzocaine, lidocaine, and tetracaine (“BLT”) applied prior to treatment with a 532-nm KTP laser resulted in significantly lower pain scores than with 3 other topical anesthetics at 15, 30, 45, and 60 minutes after application.
Cosmetic Dermatology 2003 Apr;16(4):35-7
Topical Triple-Anesthetic Gel Compared With 3 Topical Anesthetics
Iontophoresis/Phonophoresis
Iontophoresis and phonophoresis are technologies that are capable of enhancing drug penetration through the skin. Phonophoresis uses ultrasonic waves to transmit molecules of drug through the skin, as opposed to iontophoresis, which uses low-level electric current. Both techniques are used to treat inflammatory conditions such as arthritis, plantar fasciitis, tendonitis, bursitis, and carpal tunnel syndrome.
Iontophoresis: Many ionic drugs are available including several antivirals, various antibiotics, and other specific drugs. Iontophoresis of ionized drugs provided a 20-60 fold increase in penetration over topical application. Examples of successful applications of iontophoresis include:
- treatment of inflammation/pain of muscles and tendons, including the Achilles tendon
- rapid, noninvasive local anesthesia, particularly for children
- relief of heel pain from bone spurs
- controlling the pain of tennis elbow
- relief of pain from rheumatoid arthritis of the knee
- relief of pain associated with plantar fasciitis
- improvement of jaw function in patients with temporomandibular joint (TMJ) disorders
- management of hip pain in patients with sickle cell disorders (SCD)
- an alternative to steroid injections for therapy of Carpal Tunnel Syndrome
- treatment for scar and tendon adhesions
Phonophoresis (or sonophoresis) combines ultrasound with topical drug therapy to achieve therapeutic drug concentrations at target sites below the skin. A cream or gel containing medications such as corticosteroids, local anesthetics, electrolytes, or antibiotics is applied to the treatment area and then massaged with a transducer head. The technique has been widely used in sports medicine since the 1960s by podiatrists, orthopedists, and physical therapists.
The method of preparation and quality of ingredients used for solutions or gels for iontophoresis or phonophoresis are critical to the success of the therapy and minimizing side effects.
Am J Sports Med. 1997 May-Jun;25(3):312-6
Treatment of plantar fasciitis by iontophoresis of 0.4% dexamethasone. A randomized, double-blind, placebo-controlled study.
Click here to access the PubMed abstract of this article.
Examples of Compounded Medications
All formulations are customized per prescription to meet the unique needs of each patient. Please call us to discuss the dosage form, medication, and strength which are most appropriate for your patient.
- Ketoprofen topical or transdermal gel
- Ketamine transdermal gel
- Ketamine/Ketoprofen/Gabapentin transdermal gel
- Lidocaine/Prilocaine topical gel
- Triple-Anesthetic gel – benzocaine/lidocaine/tetracaine (“BLT”)
- Gabapentin/Clonidine gel
- Piroxicam tablet triturates
- Ibuprofen suppositories
- Ketoprofen/Cyclobenzaprine topical gel