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Quality of life effects of Various Transdermal Pain Therapies including compound pharma. A Paper By Dr Manish Bansal MD Jacksonville Fl

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Topical Specialist & Compound Pharmacy Study in Jacksonville FL Dr Manish Bansal MD explains the quality of life effects of various transdermal pain therapies. A multicenter prospective cohort study.
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  • 1. Quality of Life Effects of Various Transdermal Pain Therapies: A multicenter prospective cohort study Objective: To quantify the efficacy and tolerability of compounded transdermal analgesics. The transdermal pain creams included multiple pharmacologic agents with various mechanisms of action. A secondary objective was to measure the level of improvement in physical activity and exercise tolerability with these agents. Methods: We collected survey responses from 2,726 patients with acute and chronic pain syndromes and analyzed results from 1,890 patients. This was a questionnaire-based study. Participants reported results through “Topical Specialists PainAssessment Form”. Survey responses that were incomplete were eliminated from the study, which resulted in in 1,890 patients in the sample for analysis. A comprehensive statistical analysis of the data was performed. The data was evaluated for significant differences and relationship between variables. For instance, the number of oral medications usage, other pain cream usage, pain intensity, and perceived pain tolerance were studied using a paired t-test. A correlation test was performed between frequencies of cream treatment to each of the following differences: number of oral medications usage, other pain cream usage, pain intensity, and perceived pain tolerance. Results: Using a paired t-test, it was found that on average patients reported lower pain intensity after 1- 3 hours of treatment compared to before. Also, 71.1% of patients reported less pain intensity by at least two levels or more after receiving treatment. Similarly, on average patients reported higher level of pain tolerance after treatment than before. About 48.2% of patients reported greater pain tolerance of at least two levels or more after receiving treatment. Results from paired t-test analysis, showed that on average patients reduced consumption of oral medication 90 days after initiation of treatment compared to before. About 55.4% of patients reported reducing oral medication usage after receiving treatment. It was also found that on average patients reduced other pain cream usage 90 days after initiation of treatment compared to before. About 33.8 % of patients reported reducing pain cream usage after receiving treatment. Conclusion: These data demonstrate that the transdermal pain cream therapy is an effective treatment for pain intensity and tolerance. The statistical test also showed that after treatment, patients were taking fewer oral medications and reduced other pain cream usage. Keywords: medication adherence, administration, topical, patient compliance, pain, therapeutics Introduction: 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, but while also making the treatments more tolerable with fewer systemic and particularly cognitive side effects (1) 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. Despite technological advances and thorough established treatments, chronic pain continues to defy health professionals, because it is a poorly controlled condition (2). Such criteria are challenges that topical medications Abstract: **DRAFT**
  • 2. could potentially overcome, allowing progressive delivery of active component, maintaining stable plasma levels, with a good safety profile. 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 (3) (4). 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 (5). However, the role of topical pain treatments, when compared to traditional routes, has not yet been fully explored. There is, particularly a shortage of studies that quantify the effects of these agents on the patient’s quality of life. The current study aimed to use topical formulations of the most widely used drugs for pain treatment, such as nonsteroidal anti-inflammatory agents, anesthetics, muscle relaxants, neuropathic pain medications and systematically quantify both the benefits to the patients in terms of the patient’s self reported pain scores as well as the ability to increase physical activity and reduce pill burden as a result of using these treatments. The International Association for the Study of Pain defines pain as a multidimensional entity that involves nociception, afferents to the central nervous system, modulation, affective responses, endogenous analgesia, behavioral adjustments, and changes of social roles (1). While pain trigger factors are endured, pain degenerates to an independent response, manifesting even when it is possible to eradicate the primary stimulus (1). The complexity of pain management stems in part because there are three aspects involved in the pathogenesis of pain: nociception (pain sensation and topography), emotional (fear and depression), and behavioral factors (catastrophism, vigilance, and somatic awareness). Pain management faces difficulties that restrict therapeutic success, such as the limited efficiency of mono-therapy with analgesics, systemic effects, and cognitive impairment of drugs due to central effects. Chronic pain is a complex syndrome involving peripheral and central factors, justifying the prescription of multimodal therapies and drugs of central action. Evidence based on empirical practice has suggested that topically applied medications can be almost as effective as those taken orally, with a good safety profile in terms of adverse effects (1). The ultimate goal that motivates the development of topical preparations is the improvement of patient compliance to medical treatment, by providing efficient pain relief with less central nervous system effects and minimal drug regimen burden. Topical Preparations and Topical Delivery systems: Among the most widely known drugs with peripheral effects are nonsteroidal anti-inflammatory drugs (NSAIDs), anesthetics, muscle relaxants, anti- convulsants (6). Several of these agents have a primary role on the peripheral nervous system and decrease of nociceptive afferents (although some topical agents only work centrally, such as opioids). Several adjuvants such as viscosity and permeation enhancers, emollients,
  • 3. and preservatives are added to the active component, with the objective of reducing the drug concentration, increasing the absorption, maintaining the drug at the target site, and warranting less toxicity, less clearance, and greater analgesic effect (7). Topical preparations are believed to avoid issues associated with oral or intravenous routes such as gastric disturbances, first-pass hepatic metabolism, and variable serum concentrations. In addition, systemic absorption can be reduced without compromising the desired effect (1). Agents commonly used for Topical treatments: Lidocaine: Lidocaine blocks voltage-gated sodium channels, and topical administration is believed to hush ectopic discharges of fine afferent fibers. Topical lidocaine slows peripheral nociceptor sensitization and central hyperexcitability (8). Patients presenting with concurrent allodynia have been the most extensively studied in clinical trials, but analgesic benefits have also been observed in patients presenting with nonallodynic neuropathic pain. NSAIDS: NSAIDs are popular drugs and have widespread use for chronic and acute musculoskeletal conditions. They have the advantage of local action without developing central adverse effects and cognitive impairments. Within the NSAID class, each drug has a specific tissue distribution and pharmacodynamics. They block the inflammatory cascade and cyclooxygenases (COX) by inhibiting prostaglandin and thromboxane production and lead to reduction in pain, fever, platelet aggregation, and inflammatory response (9). A systematic review of topical NSAIDs for acute musculoskeletalconditions(suchasstrainsandoveruse- type injuries) studied 3455 subjects and concluded that the preparations can provide good levels of pain relief, without the systemic adverse events associated with oral NSAIDs. Positive outcomes were observed with use of diclofenac, ibuprofen, ketoprofen, and piroxicam (10). Ketamine: Ketamine is a parenteral anesthetic that provides analgesic effects in anesthetic subdoses. It is a noncompetitive N-methyl-aspartate (NMDA) receptor antagonist with opioid activity. Topical ketamine enhances local anesthetic effects of bupivacaine in nociceptive and neuropathic pain. Its analgesic effects rely on glutamate receptor activity, voltage- sensitive calcium channel blockage, interference with opioid receptors, and cholinergic and monoaminergic functions (11). Indeed, ionotropic glutamate receptors are expressed on peripheral afferent nerve terminals and membranes of unmyelinated peripheral axons, in proportion to the rate of local inflammatory response. In animal models, the increase of NMDA and non-NMDA glutamate receptors is associated with hyperalgesia and allodynia (12). Gabapentin: Gabapentin is a medication used as an anticonvulsant and analgesic. Originally it was developed to treat epilepsyandiscurrentlyusedtorelieveneuropathicpain and restless leg syndrome. It is recommended as a first line agent for the treatment of neuropathic pain arising from diabetic neuropathy, post-herpetic neuralgia and central neuropathic pain. It is a structural analogue of the inhibitory neurotransmitter γ-Aminobutyric acid (13). Several small studies have shown the efficacy of Transdermal Gabapentin for localized neuropathic pain control (14). Clonidine: Clonidine hydrochloride is generally used for oral treatment of systemic hyperten- sion; however, extensive analgesic use of oral clonidine is limited by centrally mediated side effects (sedation, hypotension, and rebound hypertension) (1). When applied topically as a cream or patch, clonidine is a potent anti-nociceptive agent that produces central and peripheral analgesic effects by blocking the emerging pain signals at peripheral terminals via alpha-2 adrenoceptors without producing the undesirable central side effects observed seen with systemic
  • 4. administration. It has been used to control hyperalgesia present in complex regional pain syndromes, likely due to the reduction of pre- synaptic norepinephrine release from sympathetic nerves (15). Tricyclic Antidepressants: Tricyclic antidepressants are considered first-line systemic therapy for many neuropathic pain syndromes, including diabetic neuropathy. Amitriptyline, nortriptyline, and desipramine have been established as analgesics independent of their antidepressant effects (16) Although their mechanism of analgesic action has not been clearly defined, tricyclic antidepressants are thought to have an inhibitory effect on nociceptive pathways by blocking the reuptake of serotonin and norepinephrine (17). Animal models of peripheral neuropathic pain have shown that tricyclic antidepressants act as sodium channel blockers, similar to local anesthetic and antiarrhythmic agents (18) Baclofen: Baclofen is a classic medication for spasticity management. It exerts its clinical effects by interacting with neurons that use gamma aminobutyric acid (GABA) as a neurotransmitter. It acts both pre- and postsynaptically to inhibit spinal reflexes (19) can be separated into groups: patient (depression and substance abuse history), contextual (social support and socioeconomic status), clinician communication skills (patient–clinician relationship), disease (chronicity and symptom burden), health care delivery (wait for appointment and medications), and treatment regimen factors (20) Several studies suggest the advantage of simplification of the regimen complexity, usually by decreasing the pill burden and dosage; while a few conclude that there is no systematic difference between the effects of changing doses and other behavioral interventions. The World Health Organization claims the main barriers to adherence related to regimen factors are high dosing and side effects. When chronic pain patients are asked about those which are the least acceptable adverse experiences related to a drug, they report central nervous system impairments (21). Topical agents are devoid of most systemic effects. Therefore, for chronic or acute localized peripheral painful syndromes, topical preparations may contribute to patient adherence, due to low incidence of collateral effects and minimal number of daily applications. Methods and Study Design: The Primary Objective of the study was to assess the efficacy of commonly prescribed transdermal pain cream formulations on improving pain scale ratings described by subjects within 1­3 hours following application. The Secondary Objective was to evaluate changes in the need for oral or other transdermal pain medications in patients who continued transdermal pain cream therapy over a period of 90 days. Physicians or their agents assessed patients using the Topical Specialists Pain Assessment Form prior to initiating pain cream therapy and up to 90 days following the date the pain cream prescription was received by the patient. Primary Outcome Variable: The Primary Outcome Variable was quality of life effects as determined by changes in patient reported pain scale, tolerability of physical activity previously limited by pain or discomfort, and incidence of adverse Medication Adherence: Adherence is defined as the extent to which the patient’s medication consumption matches the prescribed regimen. The impact of non-adherence varies across chronic illnesses, from minimal to significant. In many diseases, poor compliance to medication intake and medical advice threatens treatment outcomes (1) Several classes of correlates of adherence to long-term medication regimens have recently been identified and
  • 5. reactions. Patients were considered fully compliant with therapy if the medication was used three or four times daily for not less than three consecutive days prior to assessment. Partial compliance was indicated by medication use twice daily for not less than three consecutive days prior to assessment. Non­compliance was categorized as pain cream application less than twice daily for not less than three consecutive days prior to assessment. Secondary Outcome Variable: The Secondary Outcome Variable was alteration in the need for adjunctive pain medications. This was determined based on a review of the type and quantity of medication needed prior to initiation of pain cream therapy and up to 90 days of continual pain cream therapy of the same formulation. Compliance was categorized as indicated with the primary outcome variable. Inclusion Criteria: Subjects 18 of age and older were included in the study. Subjects were required to be experiencing either intermittent or constant pain of any nature other than visceral at the time of study enrollment. Subjects were required to have their intermittent or constant pain insufficiently relieved by pre-study therapies. It was permissible for subjects to be naïve to transdermal pain cream therapy. Pain cream formulation changes were also permissible after study enrollment. Exclusion Criteria Confirmed or suspected history of drug abuse or depen- dency was an exclusion criterion. Current incarceration or court mandated institutionalization were also ex- cluded from the study. Another exclusion criterion was discontinuation of therapy prior to 90 days due to issues unrelated to therapy adverse reactions or efficacy. Study Procedures The physician or their agent, prior to prescribing a transdermal pain cream, performed a standardized pain assessment. The provider independently chose pain cream formulations based on their individual clinical assessments. Additional assessments were performed up to 90 days after initiation of therapy, either in person or via telephone. Information obtained from these assessments or other consultations may be used to alter pain cream formulations according to the algorithm provided (see Appendix C). In the event that the pain cream prescribed is altered in its composition additional assessments will be performed at the aforementioned intervals. Time frames will be established according to receipt of the medication by the patient. Patient compliance will be evaluated by frequency and consistency of refill requests along with patient survey.Alterations in the use of oral analgesics will be determined by patient survey; institution staff may also review current prescriptions requiring renewal after initiation of pain cream therapy and note findings on the assessment form (seeAppendix B). Upon completing each assessment, information will be entered into the survey database within 7 days. Sample Size Determination The minimal detectable difference in pain scale rating, which is considered clinically significant, is 2 or more integers. Changes in physiologic functionality and exercise tolerance are considered clinically significant at a single integer (minimal detectable difference = 1). A sample size of 15 for each distinct pain cream formulation is needed for a clinically significant change in pain scale to reach the 95% confidence interval; each pain cream formulation with sufficient test subjects will be considered a cohort. Demographics of Patients In this section is a series of charts displaying descriptive information of the patients in regards to Age, Gender, Pain Type, and Pain Frequency. 3% 10% 17% 25% 25% 13% 7% 0% 5% 10% 15% 20% 25% 30% Age Distribution 18 to 24 25 to 34 35 to 44 45 to 54 55 to 64 65 to 74 75 or older
  • 6. 40% 60% Gender Proportion Male Female 24% 76% Pain Type Acute Chronic Age Frequency Percent Cumulative Percent 18 to 24 65 3.4 3.4 25 to 34 182 9.6 13.1 35 to 44 317 16.8 29.9 45 to 54 477 25.3 55.1 55 to 64 472 25.0 80.1 65 to 74 241 12.8 92.9 75 or older 135 7.1 100.0 Total 1889 100.0 Gender Frequency Percent Cumulative Percent Male 757 40.1 40.1 Female 1132 59.9 100.0 Total 1889 100.0 Pain Type Frequency Percent Cumulative Percent Chronic 1442 76.3 76.3 Acute 447 23.7 100.0 Total 1889 100.0 26% 74% Pain Frequency Intermittent Consistent Pain Frequency Frequency Percent Cumulative Percent Intermittent 498 26.4 26.4 Consistent 1391 73.6 100.0 Total 1889 100.0 3.5% 0.9% 57.1% 2.3% 17.6% 7.8% 9.7% 1.2% FID Codes 75034 75035 75039 75042 75154 75155 75212 75335 FID Frequency Percent Cumulative Percent 75034 65 3.5 3.5 75035 16 .9 4.4 75039 1045 57.1 61.5 75042 42 2.3 63.8 75154 322 17.6 81.4 75155 142 7.8 89.1 75212 177 9.7 98.8 75335 22 1.2 100.0 Total 1831 100.0
  • 7. Statistical Methods In order to determine whether the transdermal cream had a positive effect on patients’ quality of life and medication reduction, a paired t-test was performed on four different pairs of outcomes at significance level of .01. Data from the questionnaire for Oral Medication usage, Other Pain Cream usage, Pain Intensity, and Pain Tolerance were analyzed. Data was summarized according to sample sizes, mean change, and standard deviation. Further, we explained the success rate of patients who found reduction in pain intensity and medication as well increase in pain tolerance. For Pain Intensity, a patient reporting a decrease in pain scale ratings of 2 or more integers is considered a success. For Pain Tolerance, a patient reporting an increase in pain tolerance scale ratings of 2 or more integers is considered a success. For Oral Medication usage and Other Pain Cream usage, a decrease usage for any medication is considered success. It should be noted that the sample size contained 2,726 patients but only
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