Topical preparations for pain relief: efficacy and patient adherence
J Pain Res. 2011; 4: 11–24.
There has been an increasing focus on development of new routes of drug administration to provide tailored treatments for patients, without decreasing efficacy of analgesia, in proportion to the progression of the knowledge of pain mechanisms. While acute pain acts as an alarm, chronic pain is a syndrome requiring meticulous selection of analgesic drugs of high bioavailability for long-term use. Such criteria are challenges that topical medications aim to overcome, allowing progressive delivery of active component, maintaining stable plasma levels, with a good safety profile. This review presents recent findings regarding topical formulations of the most widely used drugs for pain treatment, such as nonsteroidal anti-inflammatory agents, anesthetics, and capsaicin, and the role of physical agents as delivery enhancers (phonophoresis and iontophoresis). Although the number of topical agents is limited for use in peripheral conditions, increasing evidence supports the efficacy of these preparations in blocking nociceptive and neuropathic pain. Patient adherence to medical treatment is also a challenge, especially in chronic painful conditions. It is known that reduction of treatment complexity and pill burden are good strategies to increase patient compliance, as discussed here. However, the role of topical presentations, when compared to traditional routes, has not yet been fully explored and thus remains unclear.
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Topical Analgesics in the Management of Acute and Chronic Pain
Oral analgesics are commonly prescribed for the treatment of acute and chronic pain, but these agents often produce adverse systemic effects, which sometimes are severe. Topical analgesics offer the potential to provide the same analgesic relief provided by oral analgesics but with minimal adverse systemic effects. This article describes the results of a systematic review of the efficacy of topical analgesics in the management of acute and chronic pain conditions. A literature search of MEDLINE/PubMed was conducted using the keywords topical analgesic AND chronic pain OR acute pain OR neuropathic pain and focused only on individual clinical trials published in English-language journals. The search identified 92 articles, of which 65 were eligible for inclusion in the review. The most commonly studied topical analgesics were nonsteroidal anti-inflammatory drugs (n=27), followed by lidocaine (n=9), capsaicin (n=6), amitriptyline (n=5), glyceryl trinitrate (n=3), opioids (n=2), menthol (n=2), pimecrolimus (n=2), and phenytoin (n=2). The most common indications were acute soft tissue injuries (n=18), followed by neuropathic pain (n=17), experimental pain (n=6), osteoarthritis and other chronic joint-related conditions (n=5), skin or leg ulcers (n=5), and chronic knee pain (n=2). Strong evidence was identified for the use of topical diclofenac and topical ibuprofen in the treatment of acute soft tissue injuries or chronic joint-related conditions, such as osteoarthritis. Evidence also supports the use of topical lidocaine in the treatment of postherpetic neuralgia and diabetic neuropathy. Currently, limited evidence is available to support the use of other topical analgesics in acute and chronic pain.
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Topical NSAIDs provide relief from arthritis pain
For those suffering from osteoarthritis of the knees or hands, applying topical non-steroidal anti-inflammatory drugs (NSAIDs) -- in the form of creams, gels and patches -- can bring weeks of pain relief, finds a new review by The Cochrane Library.
While oral NSAIDs are more common for managing musculoskeletal pain, reviewers wanted to examine the effectiveness of the topical variety for managing pain for longer than 8 weeks. And while they have been widely used for years in some parts of the world, topical NSAIDs have been slow to become popular in the U.S.
A team of reviewers evaluated 34 studies involving 7,688 adults with chronic musculoskeletal pain for a period of at least 3 months. Participants were organized into groups using either a topical NSAID applied at least once daily, such as diclofenac, ketoprofen, indomethacin, and ibuprofen; a placebo; or an oral NSAID.
The reviewers found the topical NSAID diclofenac was as effective as oral NSAIDs for arthritis in the knee or hand and it gave more participants good pain relief compared to the placebo in studies lasting 8-12 weeks. In four studies, for example, diclofenac gave 60 percent of participants' pain relief over 8-12 weeks compared to 50 percent of those in the placebo group.
Lead reviewer Sheena Derry, Ph.D., of the Pain Research and Nuffield Department of Clinical Neurosciences at the University of Oxford in the U.K., explained, however, that the use of topical formulations is limited to conditions where the pain is "near to the surface."
"The benefit of topical over oral NSAIDs is that with topical, the drug stays close to the site of application, so levels in blood and more remote tissues remain very low," said Derry. "This means you don't get the gastrointestinal problems that are associated and cause so many problems with oral NSAIDs."
Roger Chou, M.D., an assistant professor of medicine at Oregon Health & Science University and expert in pain management, said the review findings were similar to his past research and were consistent with what he'd expect to see.
"I think one thing to remember is that for topical medications to work, [the pain] has to be fairly localized," said Chou. "It would be tough to use these NSAIDs for fibromyalgia where the pain is all over the body, or back pain, where the pain is typically in the deeper structures."
Chou added that there are many reasons why topical NSAIDs have been slow to gain usage in the U.S., partly because the U.S. Food Administration only approved the first formulations in 2007.
"I also think that many patients and clinicians simply perceive topical NSAIDS to be weaker than pills," Chou said. "But as we learn more about their effectiveness and perhaps as the cost comes down, people will use them more."
The above story is based on materials provided by Health Behavior News Service, part of the Center for Advancing Health. The original article was written by Glenda Fauntleroy, Contributing Writer. Note: Materials may be edited for content and length.
- Sheena Derry, R Andrew Moore, Roy Rabbie. Topical NSAIDs for chronic musculoskeletal pain in adults. Cochrane Database of Systematic Reviews, 2012, Issue 9 DOI: 10.1002/14651858.CD007400.pub2
National Survey: Topical Prescription Creams Reduce Pain in Five of Every Six Chronic Pain Patients, Without Need for Opioids or Other Narcotics
BIRMINGHAM, Ala., Nov. 11, 2013 (GLOBE NEWSWIRE) -- A new survey of nearly 3,600 chronic pain sufferers nationwide reveals that more than 83 percent of them reported a significant reduction in their pain after using custom-compounded prescription pain creams, applied topically. Patients who responded to the survey said the creams were able to reduce their pain levels by more than half, on average, with more than five percent of respondents saying the creams completely eliminated their pain. In addition, 38 percent reported reducing other oral pain medications while using the creams.
The survey was conducted by Patient Outcomes Analytics (POA), a research organization, to assess patients' experience with topical prescription pain creams and their impact on the use of other oral pain medications. POA implemented an Institutional Review Board (IRB) approved protocol to survey and assess patient outcomes.
The POA survey of chronic pain sufferers around the United States found that more than 83 percent of patients queried said their pain had eased, since starting their use of the non-opioid prescription creams. In addition, they reported an average reduction of 57 percent in their pain level after directly applying the creams to the site of their pain, such as their back or neck, for the most recent 24-hour period. Using questions from the MD Anderson Cancer Center's Brief Pain Inventory (BPI), it also found that after four weeks of using the creams, patients reported significant improvement in their physical and emotional quality of life. Six percent of the patients reported minor adverse effects such as rashes.
The results demonstrate the ability of locally-applied prescription creams to deliver significant pain relief over time to many patients, without the need for patients to rely on opioids and other narcotics. This is important, given the heightened concern about what a recent Johns Hopkins University report called "an epidemic of prescription opioid addiction and abuse in the United States." The report, published in the journal Medical Care, noted that despite a "skyrocketing" use of narcotics to treat pain, "the treatment of pain has failed to improve."
In addition, the U.S. Food and Drug Administration has moved to impose tighter controls on how doctors prescribe commonly-used narcotic painkillers, like hydrocodone. The FDA, quoted in the New York Times, said prescription drugs account for about three-quarters of all drug overdose deaths in the United States, with the number of deaths from narcotic painkillers, or opioids, quadrupling since 1999. It is now recognized that opiates often magnify pain rather than reduce it. By contrast, many topical compounded prescription pain creams do not need opioids or other narcotics to be effective.
"The survey confirms what prescribing doctors have known for some time; that locally applied creams, customized and formulated to meet the specific needs of each individual, are capable of delivering significant benefits, with the potential of reducing addiction for untold thousands of Americans," said Alexis Bennett, co-principal investigator of the study for Patient Outcomes Analytics. "Given these numbers, it is intriguing that a number of Pharmacy Benefit Managers (PBMs) and third-party payors are considering denying reimbursement for these types of prescription creams."
Bennett cited a 2011 report in the journal Pain Medicine, which estimated the total societal cost of prescription opioid abuse at $55.7 billion. The report states, "The costs of prescription opioid abuse represent a substantial and growing economic burden for the society. The increasing prevalence of abuse suggests an even greater societal burden in the future." Topically applied prescription cream, Bennett said, "could ease that burden by reducing the need for narcotics while providing the relief that patients need to lead fuller lives, with the result of reduced patient pain and suffering and a reduced cost of healthcare.
"With more than 100 million Americans in chronic pain, and prescription drug abuse an epidemic, we need to employ all therapies that work and are safe to resolve the problem," Bennett noted.
Transdermal Lidocaine and Ketamine for Neuropathic Pain: A Study of Effectiveness and Tolerability
Acute neuropathic pain is a common disorder. Transdermal cream could be an alternative to oral medications.
To evaluate the effectiveness and tolerability of transdermal Lidocaine and Ketamine for acute neuropathic pain.
Retrospective chart review
University-affiliated outpatient Physiatry clinic
articipants: neuropathic pain with a prescription of a transdermal cream containing Lidocaine and Ketamine. Ef-fectiveness was evaluated by the number of patients with improvement divided by the total number of patients who re-ceived a prescription of the cream.
A total of 854 patient charts were reviewed. Twenty-one patients with symptoms, signs, and/or a documented di-agnosis of neuropathic pain and had been given a prescription of a transdermal preparation containing Lidocaine and Ketamine. Four groups were identified: those with a clearly stated diagnosis of neuropathic pain and prescribed a transdermal compound containing Lidocaine and Ketamine with follow-up (Group A) or without follow-up (Group B), and those with a suggested diagnosis of neuropathic pain with (Group C) or without follow-up (Group D). Effectiveness of the cream was seven out of eight (87%) for Group A and one out of three (33%) for Group C. In total, eight out of 11 patients (73%) benefited from a cream containing Lidocaine and Ketamine. Two patients experienced skin reactions that led to discontin-uation of treatment.
This is a retrospective chart review without control group.
Transdermal cream containing Ketamine and Lidocaine was effective in 73% of patients with acute neuro-pathic pain and may be a good alternative to oral medications.
Lipoderm® Proven to Deliver Ketamine HCl, Gabapentin, Clonidine HCl and Baclofen Simultaneously Through Human Skin In Vitro – FIRST STUDY OF ITS KIND
PCCA is dedicated to providing the very best products for your patients. PCCA is the only company that has a PROVEN transdermal delivery vehicle on the market today. Four drugs were successfully transported simultaneously through human skin, in vitro.
Evaluation of the Percutaneous Absorption of Ketamine HCl, Gabapentin, Clonidine HCl and Baclofen in Lipoderm® Into Human Trunk Skin, In Vitro, Using the Franz Skin Finite Dose Model
These four drugs were selected due to their frequent use in topical pain formulations. Until now, no study had been performed to evaluate the ability of a vehicle to deliver these actives simultaneously through human skin. Additionally, it is common for compounders to put multiple actives in a transdermal vehicle, and it is important to know that their vehicle is actually capable of delivering more than one active. The study was designed to evaluate the percutaneous absorption pharmacokinetics of ketamine HCl, gabapentin, clonidine HCl and baclofen. Absorption was measured in human cadaver skin, in vitro, using the finite dose technique and Franz Diffusion Cells, a specific study design that is the gold standard in the pharmaceutical industry. This study resoundingly demonstrates that Lipoderm® has the power and reliability compounders are looking for.
The products were tested on replicate sections from three different cadaver skin donors, for the percutaneous absorption of ketamine HCl, gabapentin, clonidine HCl and baclofen over a 48-hour dose period. At pre-selected times after dose application, the dermal receptor solution was removed in its entirety, replaced with fresh receptor solution, and an aliquot saved for subsequent analysis. In addition, the epidermis and dermis were recovered and evaluated for drug content. The samples were analyzed for ketamine HCl, gabapentin, clonidine HCl and baclofen content by High Performance Liquid Chromatography (HPLC)/MS.
Methods and Procedures
Percutaneous absorption was measured using the in vitro cadaver skin finite dose technique. Human cadaver trunk skin without obvious signs of skin disease, obtained within ~24-48 hours of death, was used in this study. Skin from three donors was cut into multiple smaller sections large enough to fit on static 1.0 cm2 Franz diffusion cells. To assure the integrity of each skin section, its permeability to tritiated water was determined before application of the test products. All formulations were then applied to the skin sections using a positive displacement pipette set to deliver 5 μL formulation/cm2. The dose was spread across the surface with the Teflon® tip of the pipette. At preselected times after dosing (2, 4, 8, 12, 24, 32, and 48 hours), the reservoir solution was removed in its entirety, replaced with fresh reservoir solution, and an aliquot saved for subsequent analysis.
The data indicate that PCCA’s Lipoderm® delivered ketamine HCl, gabapentin, clonidine HCl and baclofen, simultaneously (and intact), into and through human cadaver skin, in vitro. The absorption profiles indicate a rapid penetration to a peak flux for gabapentin and baclofen occurring approximately one (1) hour after dose application, and approximately four (4) hours for ketamine HCl. Clonidine HCl exhibited a rapid penetration to an initial peak flux occurring one (1) hour after dose application, but also a secondary peak at approximately 40 hours, possibly due to a depot of some of the applied dose in the epidermis. This one-of-a-kind study validates the ability of Lipoderm® to deliver four drugs simultaneously through human skin. This information is of great value for pharmacists and physicians utilizing topical preparations for various pain syndromes.
Download the complete PDF detailing the results of this study.
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