Dr James Schaller
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Transdermal Orthopedic USP Cream
for Arthritis Joint Pain

Arthritis is the leading cause of physical disability in the United States, with the most common form being osteoarthritis. Arthritis costs $51 billion in medical costs and $86 billion in total costs. The Center for Disease lists 49 million American adults report doctor-diagnosed arthritis and another 21 million report chronic joint symptoms (2001). The number of people age 65 and older who have arthritis or chronic joint symptoms is projected to nearly double from 21.4 million in 2001, to 41.4 million in 2030 as the population ages.1 Part of the solution to joint pain and further joint degeneration is activity, exercise and weight loss, but pain can limit this option.

While osteoarthritis is the most common form of arthritis, it has not yielded simple causes or treatments. It is a complex disease whose etiology ranges from biomechanics to biochemistry. Evidence is growing for the role of systemic factors, such as genetics, diet, biotoxins, miscellaneous hormones, bone density, and local biomechanical factors, such as muscle weakness, obesity, and joint laxity. Attempts to reduce pain and disability are yielding diverse treatments including: nutraceuticals, chondrocyte transplantation, new oral anti-inflammatory medications, health education, acupuncture, exercise, bracing, behavioral interventions to enhance self-management, and a wide range of surgical approaches, with some biotechnology-oriented approaches on the horizon. Certainly the treatment goal is to use multi-model interventions to control pain and improve function and the quality of patient life, while avoiding therapeutic toxicity. Since many arthritis sufferers are older patients with decreased hepatic and renal function, this is not always a simple task.2

One treatment option we believe is significantly underutilized is high dose, multi-component transdermal compounded prescription medication. We believe it may be superior to transdermal and common oral non-prescription agents.

By transdermal, we are not suggesting the agents commonly seen over-the-counter and in commercials, such as capsaicin cream or topical salicylates for mild or moderate arthritis pain (used alone or as adjunctive treatment).3 While these have some utility, our concern is that self treating with non-prescription transdermal forms, does not offer maximum benefit found with synergistic prescriptions. Further, some patients may use excess doses of single agent formulas, e.g., salicylates, with potentially fatal doses of transdermal or topical dosing.4 Other common options used to self-treat or prescribed include non-steroidal anti-inflammatory drugs (NSAIDS) that cause a number of serious consequences including peptic ulcer deaths, interactions with common medications (oral corticosteroids, anticoagulants, angiotensin-converting enzyme inhibitors), and possible renal injury. We are also concerned with micro inflammation of the intestines, not merely the stomach.

While new COX-2–specific inhibitors are reported to be safer one the intestinal track, as with nonselective NSAIDs, COX-2–specific inhibitors can cause renal toxicity.

One final transdermal option, is the transdermal Lidocaine patch, which is a significant contribution to the treatment of pain, nevertheless, has a fairly low dose limit of three patches, since it is an antiarythmic. Large amounts applied by confused pateints or suicidal pateints could be fatal. More commonly, the cloth-like patch would not be functional on some common arthritis areas such as the fingers. It is also visable if used on the face, e.g., for post dental surgery, while a penetrating cream is not visable. Our experience is that pateint s who have failed the lidocaine patch have successfully been treated with one of our transdermal pain creams, unless the pain was in a very deep joint such as the hip. We have not done controlled trials comparing these prescription creams with lidocaine patches.

In this context, we believe that multiple prescriptions with different target mechanisms at modest doses are an important option in the treatment of arthritis.

Compounding Medications and
the Politics of Prescription Manufacturing

The FDA does not regulate prescriptions produced by compounding pharmacists since these are not manufactured prescriptions. State boards of pharmacy regulate the skill of professional compounding pharmacy. Aggressive transdermal options with multiple prescription ingredients are not offered or promoted by pharmaceutical companies. We are not aware of a single promoted arthritis cream or gel made from United States Pharmacopoeia (USP) powders, that offers multiple prescriptions in a single transdermal form. For example, it is unlikely that three or four pharmaceutical companies with prescription powders would agree to be involved to combine their powdered medications to make a single treatment cream. Realistically, they are unlikely, currently, to come to a mutual agreement on a product.

But compounded prescriptions are not limited by pharmaceutical options, product line or business decisions. These issues do not limit our formulas. These formulas also appear to be quite effective on many joints.

We have comprised 3 topical pain management formulas to assist in alleviating acute and chronic pain.

Pain Formula Creams

  1. Pain Formula Cream #1
    1. 6% Gabapentin USP, 0.2% Clonidine HCl USP, 20% Ketoprofen USP, 2% Amitriptyline HCl USP in PCCA Lipoderm™ base.
  2. Pain Formula #2 with Ketamine
    1. 2% Ketamine HCl USP, 6% Gabapentin USP, 0.2% Clonidine HCl USP, 20% Ketoprofen USP, 2% Amitriptyline HCl USP in PCCA Lipoderm™ base.
  3. Diclofenac/DM/Piroxicam Cream
    1. 8% Diclofenac USP, 4% Dextromethorphan USP, 4% Piroxicam USP in PCCA Lipoderm™ base
    2. <

Discussion

The first 2 formulas are very similar except for the ketamine.

Pain formula #1 contains:

2% amitriptyline
0.2% clonidine HCl
6% gabapentin
20% ketoprofen.

Pain formula #2 is the same except that 2% ketamine is added. (We have occasionally used 6-10 % ketamine, but these higher doses are not included in the research below).

Both are prepared in Professional Compounding Centers of America (PCCA) Lipoderm™ base. Amitriptyline is a tricyclic antidepressant with clinically proven efficacy in several pain conditions. It has the ability to antagonize sodium channels, which may explain its local anesthetic effect.8 Dosing of the older antidepressant is not for systemic use or effects, but only for local absorption to targeted tissues. Clonidine is a _-2 receptor antagonist that has demonstrated analgesic properties in patients with sympathetically maintained pain (SMP).9 Despite its analgesic effect, no anesthetic properties have been found with clonidine. Gabapentin is a anticonvulsant medication that has been studied as a treatment for diabetic neuropathy and post-herpetic neuralgia.10,11 Ketoprofen is a non-steroidal anti-inflammatory drug (NSAID) that has been proven to be effective topically for pain and inflammation.12 Ketamine is an NMDA-receptor antagonist that produces its anesthetic effect by blocking afferent pain impulses at the local tissue level. Due to the potential for psychiatric side effects, the ketamine is kept at functional and for local effects, to avoid central nervous system problems like hallucinations.13

Pain formula #3 contains:

8% diclofenac
4% dextromethorphan
8% piroxicam

Again, these are dissolved into a PCCA Lipoderm™ base. Diclofenac is a non-steroidal anti-inflammatory that has been shown to have topical analgesia.14 Dextromethorphan (DM) is a non-narcotic antitussive that possesses NMDA-receptor antagonist properties. Local tissue deactivation of the NMDA receptor leads to increased duration of pain relief; therefore antagonists of this receptor may enhance pain relief.15 Piroxicam is also a non-steroidal anti-inflammatory drug that has shown efficacy in pain syndromes such as migraine headaches.16 Piroxicam possesses both analgesic and anti-inflammatory properties.

All three creams are in a PCCA Lipoderm™ base. It was chosen because PCCA Lipoderm™ contains a patented liposomal component that provides the system with a Chemical Penetration Enhancer (CPE) value comparable to a pluronic lecithin organogel (PLO) and speed gel. Lipoderm™ allows the medication to reach the system's circulation and local areas with efficiency. It is a stable system, which does not separate upon refrigeration or in the presence of ionic substances.17

Patient Trials of Pain Formulas 1 & 2

In the use of our two pain relief joint transdermal creams, we followed the follow procedure. Patients were offered these two options only if they were unsatisfied with their current treatment. All patients were either offered a 10-ml trial dose of cream or a full prescription trial, but all began with a full dose of 2 mL per am and qhs applied to their most painful joints. (No one was allowed to use over 8 mls/day). Their prescription was picked up or mailed to them. We had to mail their cream at times because they were pleased with effect and did not want to change their prescription.

Patient Reports

Seventy-eight patients over six years received the first two pain formulas. Acute injury patients were not included in this number. Some patients had more than one joint with arthritis and so the numbers are in excess of the patient totals. No patient was included who did not take the cream continuously for 3 days. Specifically, eight patients said they "were distracted," "too busy to try," or "could not afford the cream." The later were offered insurance receipts but still wanted to pursue other options, such as cortisone injections or surgery.

Patient reports were rated very simply. Patient's who reported "no benefit" or "mild benefits" were counted as fully unsuccessful negative trials.

The cream was only considered successful or a positive treatment, if the patient reported "a moderate yet clear benefit," a "considerable benefit" or "a remarkable benefit."

Pain SourcePositive ReportNegative Report
Neck1225
Shoulder96
Elbow152
Wrist182
Fingers310
Hip05
Middle Back810
Lower Back209
Knee4614*
Ankle132
Foot165**

*Knees that were fully negative in outcome were all profoundly diseased joints. Specifically, nine were pre-knee replacement patients and the rest had MRI's and/or orthopedist determinations reporting profound cartilage absence.

**The effectiveness on feet was largely determined by the degree of callous on the skin closest to the source of the pain and the distant from the skin to the pain. Individuals with significant callus and pain that seemed to be arising from the bottom of the foot or sole, generally had no significant benefit. Conversely, individuals with pain sources on the top of the foot or which was close to the skin surface without callous, generally had a positive response.

Clearly, joints with easy transdermal access to bone and deep soft tissue such as fingers had high success. Joints that were deep and poorly accessible, such as hip joints offered not help. As a trend, the thinner the patient's body the greater benefit. However, some heavy patients with thick-skinned backs reported benefits, and other patients with markedly thin back tissue had no benefit. We suspect some thinner patients had more marked spine pathology.

We did not use a side-effect questionnaire, but did request at least twice of every patient, if they noted "any side effects or any problems" over their baseline functioning. These were asked in an open-ended manner. However, patients were asked directly about orthostatic hypotension, dry mouth, and vision changes, along with personality and perception changes. No patient reported any side effect over his or her baseline. This includes both responders and non-responders.

Individuals with a positive response to these pain creams virtually all continued to use it daily. The majority of those that stopped had joint replacement surgery and had only one painful joint, or were diagnosed with a reversible cause, e.g., Lyme disease. Meaning, from the time of their first trial until the current time. Even individuals with joint replacements, typically continued to use these pain formulas on their lesser arthritic joints.

Pain Formula #3 Results

Pain formula #3 was developed after the authors were frustrated at the high degree of pain some dental surgery patients were experiencing. We observed the under treatment of pain or NSAIDS that were associated with side effects or were ineffective. Pain formula #3 was only used after a an oral lidocaine 10%/ tetracaine 0.5% spray was unsuccessful when delivered near to the mucosa nearest the pain. This cream formula was used if bone pain was felt to be involved, e.g., post tooth extraction with a necrotic root and abscess. This formulation was applied to the jaw at the site of pain on the outer facial skin, 3 mls q 12 hours. While our expectations were modest, e.g., due to the hypovascular nature of the jawbone, all nine patients reported a 70-95% decrease in pain. While this was not a blinded test, their reaction of relief seems to warrant some consideration for future study. Four of the patients were required to undergo further dental surgery, and all four requested prescriptions and information to give their dentist.

In conclusion, compounded prescriptions offer wonder options in medical treatment. Compounding has a strong past in allopathic medicine and should be one tool physicians use weekly. Compounders offer hundreds of options unavailable from drug companies which would fit your needs better.

References

  1. www.cdc.gov/od/oc/media/pressrel/fs040513.htm. Accessed 19 May 2004.
  2. DT Felson, RC Lawrence, et al., Osteoarthritis: new insights--part 2: treatment approaches. NIH Conference. 2000; 133: 726-737.
  3. Tramer MR. It ™s not just about rubbing—topical capsaicin and topical salicylates may be useful as adjuvants to conventional pain treatment. British Medical Journal. 2004:328:998.
  4. Mason L, Moore RA, Derr S, Edwards JE, McQuay, HJ. Systematic review of topical capsaicin for the treatment of chronic pain. British Medical Journal. 2004:328:991.
  5. Mason L, Moore RA, Edwards JE, McQuary HJ, Derry S, Wiffen PJ. Systematic review of efficacy of topical rubefacients containing salicylates for the treatment of acute and chronic pain. British Medical Journal 2004;328:995
  6. Chan TY. The risk of severe salicylate poisoning following the ingestion the ingestion of topical medicaments or aspirin. Postgaduate Medical Journal. 1996;72:109-112.
  7. Chan TY, Chan AY, Ho CS, Critchley JA. The clinical value of screening for salicylates in acute poisoning. Vet Hum Toxicol. 1995;373-38.
  8. Gerner P, Kao G, Venkatesh S, et al. Topical amitriptyline in healthy volunteers. Reg Anes & Pain Med. 2003: 28:289-93.
  9. Davis KD, Treede RD, Raja SN, et al. Topical application of clonidine relieves hyperalgesia in patients with sympathetically maintained pain. Pain. 1991: 47:309-17
  10. Backonja M, Beydoun A, Edwards KR, et al. Gabapentin for the symptomatic treatment of painful neuropathy in patients with diabetes mellitus. JAMA. 1998 Dec; 280(21): 1831-6.
  11. Rowbotham M, et al. Gabapentin for the treatment of postherpetic neuralgia. JAMA. 1998 Dec; 280(2): 1837-42.
  12. Osterwalder A, et al. Tissue absorption and distribution of ketoprofen after patch application in subjects undergoing knee arthroscopy or endoscopic carpal ligament release. Arzneimittelforschung. 2002; 52(11): 822-7.
  13. Backonja M, Arndt G, Bombar KA, et al. Response of chronic neuropathic pain syndromes to ketamine: a preliminary study. Pain. 1994; 56: 51-7.
  14. Burman R, et al. The effectiveness of topical diclofenac for lateral epicondylitis. Clin J Sport Med. 1998 Apr; 8(2):78-81.
  15. Hewitt DJ. The use of NMDA-receptor antagonists in the treatment of chronic pain. Clin J Pain. 2000 Jun; 16(2 Suppl): S73-9.
  16. Nappi, et al. Effectiveness of a piroxicam fast dissolving formulation sublingually administered in the symptomatic treatment of migraine without aura. Headache. 1993 Jun; 33(6): 296-300.
  17. Excerpted from PCCA Bases Literature


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