International journal of pharmaceutical compounding
Clinical Nuggets and Pearls:Chronic Neuropathic Pain
and Opioid Tolerance
Marty Jones, BS Pharm, FACA, FIACP
gardless of the degree, resolves when tissues tem (CNS), but chronic pain is primarily Professional Compounding Centers of heal and is usually a short-term problem.
the result of a neuropathic injury or mod- America, Inc, Houston, Texas Chronic pain, which is a disease state in it- ulation within the CNS. self, may persist for months or years. Acute Pain is ameliorated by a variety of med- pain, which is intense or severe, is usually ications, among which are opioids, nonste- of rapid onset and brief in duration. Pain de- roidal anti-inflammatory drugs (NSAIDs), Pain is the noxious, unpleasant sensation fined as "chronic" can be of any intensity and steroids. Chronic pain can be caused by perceived as a result of disease or injury that but must persist for 3 months or longer.
malignant or nonmalignant diseases. Chron- stimulates certain nerve fibers, which relay Acute pain usually involves brief noci- ic or acute pain that results from a malig- that stimulus to the brain. Acute pain, re- ceptive input to the central nervous sys- nant condition is usually relieved by opioid Table 1. Algorithm for the Treatment of Chronic Neuropathic Pain.1
Route of Administration
Drug or Drug Class
Reported at 5% and 10% ————— Other mu agonists also; wide dosage range ———— TNF-1α antagonist Pentoxifylline 2% to 16% depending — on the size of the treated area Carbamazepine (?) NMDA = N-methyl-D-aspartate TNF-1α = Tumor necrosis Historically, treatment with ketamine, gabapentin, and clonidine is ? = Drug or drug class undetermined initiated as described above. Then one or more of the other drugs is β = γ-aminobutyric acidβ Modified December 2001. International Journal of Pharmaceutical Compounding Vol. 6 No. 1 January/February 2002 therapy; however, some patients become opi- patient's quality of life. It is well docu- oid tolerant. Opioids often do not provide mented in the literature6,7 that NMDA an- relief from acute or chronic pain caused by Patients who are opioid tolerant require tagonists (ketamine, dextromethorphan) a nonmalignant condition, and the man- escalating doses of their therapeutic drug are useful in decreasing opioid tolerance. In agement of those types of pain is more in increased strength or frequency or both the following protocol, the use of NMDA complicated. In the United States, the use to achieve the same degree of pain control antagonists to reduce opioid load is pre- of opioids to treat chronic nonmalignant as that previously provided by a lower pain has been subject to criticism, and the dose. Side effects caused by opioid treat- Step 1. Inform the patient and/or caregivers
literature is replete with consensus that ment are also a clinical concern, as is the of the intent to reduce the dose of the chronic neuropathic pain does not respondto opioids. Currently, negative informa-tion on the use of oxycodone (OxyContin) Figure 1. Map of the Human Dermatomes.
has generated new awareness of the prob-lems associated with opioid use.2,3 SPINAL CORD
The treatment of chronic neuropathic pain requires the use of medications such as N- methyl-D-aspartate (NMDA) receptor an- tagonists, glutamate antagonists, α-2 ago- nists, sympatholytics, γ-aminobutyric acid (GABAβ) agonists, mu receptor agonists,1 and tumor necrosis factor-1α (TNF-1α) antag- onists,4 which are not usually indicated for that purpose. As a mu agonist, methadone displays very weak NMDA antagonist ac- tion.5 Historically, pain has been addressed pharmacologically with oral, parenteral, rectal, or transdermal monotherapy. How- ever, the multifaceted nature of chronic neuropathic pain requires a departure from those treatments. Today, many compound- ed topical medications are used to treat chronic neuropathic pain effectively. The re- cent use of multifaceted regimens of topi- cally applied medications has been anecdo- tally reported as being successful (MJ, oralcommunication, 1995 – present). An algo- rithm such as that featured in Table 1 for the treatment of chronic neuropathic pain canbe implemented successfully by com- pounding pharmacists. The base of choicethat I currently prefer for use with that al- gorithm is Lipoderm Base (Professional Compounding Centers of America, Inc [PCCA], Houston, Texas). A correctly com- pounded Pluronic lecithin organogel (PLO [PCCA]) or VanPen Base (PCCA) is also ef- viewed from the front
viewed from the side
fective.1 When such topical compounds areapplied 3 times daily on a regular basis to thepain site and to the corresponding dorsal hornof the dermatome involved (Figure 1) as This map can be used to trace an afferent nerve fiber from the periphery to the dorsal well as every hour or two when needed, the horn of the dermatome involved. results are very positive. International Journal of Pharmaceutical Compounding Vol. 6 No. 1 January/February 2002 dorsal horn of rats prevented compartment syndrome. Yabuki et Table 2. A Comparison of Side Effects Caused by
al8 concluded that pentoxifylline might prevent sciatica caused by Opioids or NMDA Antagonists.
a herniated disk. Pentoxifylline also has been administered oral-ly (400 mg every 8 hours) to prevent sunburn because it blocks NMDA – Antagonist-Related
the ultraviolet B (UVB) light apoptosis of keratinocytes.9 If Side Effects
Side Effects
TNF-1α is involved in the release of other cytokines of inflam-mation and that action is local, then the local application of pen-toxifylline should be a useful adjunct to a neuropathic regimen, particularly in the treatment of low-back pain. It should also be useful in diminishing or preventing sunburn pain when used as a local preapplication to sunbathing.
Increased blood pressure Loperamide: A Topical Mu Agonist
Respiratory depression Loperamide, a mu agonist,10 is administered orally to control di- arrhea. It exerts a local effect on the gastrointestinal tract, and it produces few side effects that affect the central nervous system. Thelow oral dose of efficacy indicates the potency of loperamide as a mu agonist. It is well reported in the literature11,12 that mu recep- tors are found in the skin. It is then logical to add loperamide to a Paranoid schizophrenic behavior topical regimen for chronic neuropathic pain when a mu agonist NMDA = N-methyl-D-aspartate is desired. This provides mu agonist action without the need for anarcotic mu agonist such as morphine.
opioid and provide instructions about reporting potential or expected side effects, such as those listed in Table 2. Jones M. Chronic neuropathic pain: Pharmacological interventions in Step 2. Change all long-acting (sustained release, extended release,
the new millennium: A theory of efficacy. IJPC 2000;4:6-15.
and transdermal delivery system) mu agonists (morphine, oxycodone, 2. Chernin T. Painkillers and pill popping. Drug Topics 2001;145:31-41. fentanyl) to immediate-release (IR) dosages. Usually, this is ac- 3. Ukens C. High alert: OxyContin thieves target pharmacies. Drug Topics complished by using equipotent equivalencies taken from published conversion charts. Sullivan GW, Carper HT, Novick WJ Jr, et al. Inhibition of the inflammatory Step 3. Initiate therapy with an orally administered NMDA an-
action of interleukin-1 and tumor necrosis factor (alpha) on neutrophil function by pentoxifylline. Infect Immun 1988;5:1722-1729. tagonist (a compounded 10- or 15-mg capsule administered 2 or 3 Carpenter KJ, Chapman V, Dickenson AH. Neuronal inhibitory effects of times daily). Increase the dose by 1 capsule every 2 days until the methadone are predominantly opioid receptor mediated in the rat spinal opioid requirement (expressed as potential or expected side cord in vivo. Eur J Pain 2000;4:19-26.
effects) is reduced. Kane DL, Glasnapp, A. Dextromethorphan hydrobromide and opioid Step 4. Reduce the opioid dosage 30% and monitor the patient's
tolerance: A compounding opportunity for pharmacists with chronic pain patients. IJPC 1998;2:118-119.
condition and the degree of pain control achieved. Crowley KL, Flores JA, Hughes CN, et al. Clinical application of ketamine Step 5. When the patient's condition is stable and the pain has been
ointment in the treatment of sympathetically maintained pain. IJPC 1998:2: controlled, repeat step 3 (but increase by 1 capsule from the cur- rent dose) and step 4 until the level of opioid desired is achieved, Yabuki S, Onda A, Kikuchi S, et al. Prevention of compartment syndrome the patient remains comfortable, and pain is controlled.
in dorsal root ganglia caused by exposure to nucleus pulposus. Spine2001;26:870-875.
Step 2 is critical to the success of step 4. The opioid must be in Lowitt MH. Pentoxifylline attenuates UVB-induced cutaneous erythema. an IR form to enable immediate reduction of the opioid dosage. As the dosage of the NMDA antagonist increases, so does the risk of 10. Nozaki-Taguchi N, Yaksh TL. Characterization of the antihyperalgesic side effects. If serious side effects occur before the opioid dosage action of a novel peripheral mu-opioid receptor agonist — Loperamide. is reduced, the patient may be too sensitive to the NMDA antag- Anesthesiology 1999;90:225-234. onist. If the attempt to reduce the opioid dosage is made again, titrate 11. Bigliardi-Qi M, Buechner S, Rufli T. Expression of mu-opiate receptor in human upward with longer intervals between escalations of the dosage. epidermis and keratinocytes. J Invest Dermatol 1998;111:297-301.
12. Thompson DF, Pierce DR. Local analgesia with opioid drugs. Ann Pharma- Pentoxifylline Blocks TNF-1α
Pentoxifylline is a known TNF-1α antagonist.4 TNF-1α is a key Address correspondence to: Marty Jones, Professional Compound- pathogenic factor in the initiation and maintenance of neuropathic ing Centers of America (PCCA), Inc, 9901 S. Wilcrest, Houston, pain states. Direct local application of pentoxifylline to the TX 77099. E-mail: [email protected] ■ International Journal of Pharmaceutical Compounding Vol. 6 No. 1 January/February 2002
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