Pain Management References
 
Pain Management Overview

The routes of administration of the various pain formulas vary including topical gels and creams, solutions for iontophoresis, oral capsules (regular and sustain release), sublingual and buccal tablets, nasal sprays, rectal suppositories, and injectables.

As a compounding pharmacy, we have prepared a wide range of medications from relieving the acute pain of severe sunburns with low dose topical ketoprofen gels to the severe bone pain of cancer metastasis that were unrelieved by morphine, Duragesic or OxyContin. The Gels we use the most contain various combinations and strengths of Bupivicaine or Lidocaine, Clonidine, Dextromethorpan, Gabapentin, Ketamine, Pentoxifylline, Amitriptylline, and Ketoprofen.

We use a wide range of transdermal bases to transport the medications through the skin. We prepare the first generation Pluronic Lecithin Organo gel (PLO), a Vanishing Lecithin Organo gel (VLO), a proprietary Vanishing Penetrating Cream (VPC), Speed Gel, and various anhydrous gels.

Generally we use the first generation PLO gels less because they leave a sticky residue many of our patients find unacceptable. The VPC gels are more acceptable and equally are more effective. The speed gel is a fluid transdermal gel that is well suited to deliver medications to an area such as the ear. We treated an 84-year-old female patient with neuropathic pain shooting from the roof of her mouth diagonally into her eye. After consulting with the physician, who did not want to use injections because of her age and the fact that they would also be invasive, we decided to use a mixture of Bupivicaine, Gabapentin and Ketamine to treat her pain. We decided to use a flavored PLO gel, because of its sticky nature, as the vehicle and apply it under her denture. About an hour after leaving the pharmacy, the lady called and reported that 97% of her pain was gone. I feel this case is an excellent demonstration of the working partnership of Physician, Patient and Pharmacist in solving an individual’s unique problem.

Chronic neuropathic pain results from many origins that result in functional changes due to diseases (e.g. diabetic peripheral neuropathy, post herpetic neuralgia, complex regional pain 
syndrome type I [formerly RSD], fibromyalgia, post-surgical neuropathy, post-trauma neuropathy and neuropathies with no known cause) and share the same pathway of sensory input and central recognition. Compounding allows the physician to choose multiple drugs to affect these pathways with different mechanisms of actions to increase efficacy while decreasing adverse drug reactions.

One concern of physicians treating patients with chronic pain is the patient’s exposure to acetaminophen, which not only may be in their pain medications but also in many over the counter products. We can compound the medications acetaminophen free, with non-steroidal anti-inflammatory drugs (NSAIDs) (e.g. Ketoprofen, Ibuprofen or Dextromethorpan). An example of a Dextromethropan/Hydrocodone dose might be Dextromethropan 60mg, Hydrocodone 5 mg capsule. There are two primary advantages to this product. First, the physician has eliminated the acetaminophen; the combination remains a class III drug since the dose of dextromethropan is therapeutic. Dextromethorpan (DM) is a N-methyl-d- aspartate (NMDA) receptor antagonist which allows the opioid dose to be reduced by 40% to 60% to reduce side effects of high opioid doses. Secondly, for cancer patients or patients on long term high dose opioid therapy, the physician can introduce DM to the dosage regimen, titrating the DM up while titrating the opioid down until there is adequate pain relief without side effects.

We have the training, expertise, chemicals, equipment and certified clean room to work with you physician to tailor a medication to relieve your pain.


Pain Management References

Clin Ther. 2006 Oct;28(10):1607-18.

Dextromethorphan and quinidine in adult patients with uncontrolled painful diabetic peripheral neuropathy: a 29-day, multicenter, open-label, dose-escalation study.  
Thisted RA, Klaff L, Schwartz SL, Wymer JP, Culligan NW, Gerard G, Pope LE, Berg JE.

Department of Health Studies, The University of Chicago, Chicago, Illinois 60637, USA. r-thisted@uchicago.edu

BACKGROUND: Pain associated with diabetic peripheral neuropathy (DPN) has a substantial negative impact on patients' quality of life. OBJECTIVES: The primary objective of this study was to evaluate the tolerability of capsules containing dextromethorphan (DM) and quinidine (Q) in patients with painful DPN. A secondary objective was to perform a preliminary assessment of the efficacy of DM/Q in this patient population. METHODS: This was a multicenter, open-label, dose-escalation study. Eligible patients were aged between 18 and 80 years, had a confirmed diagnosis of diabetes with acceptable glycemic control, had been receiving established diabetic therapy for at least 3 months, and had a clinical diagnosis of distal symmetric sensory neuropathy with daily DPN-associated pain for the previous 3 months. On study entry, patient-rated diabetic pain had to be moderate or greater. Patients who met the inclusion criteria underwent a 2-week washout period during which all analgesics were discontinued, followed by 29 days of treatment with capsules containing DM 30 mg and Q 30 mg (DM30/Q30), beginning with 1 capsule/d and escalating at approximately 1-week intervals, as tolerated, to a maximum dose of 4 capsules/d (DM120/Q120). Tolerability was assessed based on adverse events and changes in clinical and laboratory parameters and nerve conduction velocity. Preliminary efficacy assessments included changes from baseline in scores on the pain intensity rating scale (PIRS), pain relief rating scale (PRRS), peripheral neuropathy quality-of-life instrument, and patients' diary assessments of sleep, present pain intensity, pain, and activity. RESULTS: The study included 36 men and women (mean age, 58 years; mean body mass index, 32.8 kg/m(2)). Of the 33 subjects who completed the study, 23 (69.7%) did so at the highest permitted dose (DM120/Q120). The most commonly reported adverse events (occurring in > or =5% of subjects) were nausea (27.8%), dizziness (25.0%), and headache (25.0%). Three patients experienced 5 serious adverse events, only 1 of which was considered possibly related to study drug. The most commonly occurring laboratory abnormalities (involving glycosylated hemoglobin, serum glucose, triglycerides, and cholesterol) were considered typical of a population with diabetes. Improvements from baseline in scores on the PIRS, PRRS, and other exploratory efficacy measures were noted (P < 0.001). CONCLUSIONS: The results of this open-label study indicated that the combination of DMIQ (dose range, DM30/Q30-DM120/Q120) was well tolerated in patients with pain associated with DPN. Based on the preliminary efficacy results, a randomized, controlled, double-blind trial is warranted to assess the tolerability and efficacy of this combination in patients with DPN.

PMID: 17157116 [PubMed - indexed for MEDLINE]



IJPC VOL 2 # 2 MARCH/APRIL 1998
Dextromethorphan Hydrobromide and Opioid Tolerance: A Compounding Opportunity for Pharmacists with Chronic Pain Patients
Author(s):Kane, Dana Lynn; Glasnapp, Andrew
The authors discuss opioid tolerance and the mechanisms of action responsible for it and show how dextromethorphan hydrobromide can be used to block this tolerance. The discussion includes its chemical characteristics, dosing/formulation considerations and storage/stability. A table provides information regarding Dextromethorphan Hydrobromide USP Capsules (Quantity: 100).

IJPC VOL 2 # 1 JANUARY/FEBRUARY 2000
Chronic Neuropathic Pain: Pharmacological Interventions in New Millennium
Author(s):Jones, Marty
Recent reports of N-methyl-D-aspartate receptor antagonists, glutamate antagonists, alpha2-agonists, gamma-aminobutyric acid agonists, alpha1-antagonists, opioids and antioxidants in various combinations provide the contemporary rationale that is furnishing increased efficacy in the clinical management of chronic neuropathic pain, with fewer side effects. This article focuses on this new theory as an approach, from the perspective of a compounding pharmacist, to provide better control of chronic neuropathic pain in the new millennium. Implementation of this theory in daily practice within the triad of care will enhance the odds of positive outcomes in patients suffering from chronic neuropathic pain. The author focuses on pathophysiology, evidence, a new approach and clinical compounding success. He concludes that this is a huge market and that the efficacy is significant using the approach presented in this article.

IJPC VOL 3 # 6 NOVEMBER/DECEMBER 1999
Iontophoresis and Phonophoresis for Treating Epicondylitis
Author(s):Miller, DeWayne; Vann Pat, with Hudson, Sonora
The authors present two case reports of successful treatment of patients with epicondylitis using dexamethasone delivered by iontophoresis and/or phonophoresis. The first involves a 52-year-old golfer with a diagnosis of severe, chronic right lateral epicondylitis with some tearing. He was treated for 9 weeks, with three visits to physical therapy each week, which involved iontophoresis with desamethasone sodium phosphate solution, moist heat, phonophoresis with dexamethasone USP and massage. Treatment also included exercise, which the patient performed once at his therapy sessions and twice independently at home, applying an ice pack after each series of exercises. His recovery was excellent, with all bruising and swelling resolved and good strength and motion, enabling him to resume normal activities of daily living. In the second case report, the patient worked on a manufacturing production line and presented with left-wrist tendinitis due to work-related activities. She was treated for 2 weeks with three visits per week that included iontophoresis with dexamethasone sodium phosphate solution, moist heat and ultrasound. Exercises were performed once at therapy sessions and twice at home, followed by deep-friction massage and ice to the affected area. The patient had improved after 2 weeks but required another week of treatment. At that time, she experienced 85% improvement and reported very little numbness and tingling in her forearm and hand. The authors conclude that del

IJPC VOL 2 # 2 MARCH/APRIL 1998
Managing Pain in the Terminally Ill
Author(s):Williams, Clifford, L.
The purpose of this article is to present a case that illustrates the basics of pain management. The author is a palliative-care specialist and hospice medical director. The case involves a 57-year-old man who was diagnosed with large-cell carcinoma of the lung. The patient was eventually treated with a compounded suppository of haloperidol + metoclopramide + dexamethasone until the final stages of his illness, when he was switched to hydromorphone given as a continuous subcutaneous infusion. His expiration was peaceful. The author discusses the principles of pain management applied to this case. A table provides information regarding opiate equivalents. The author concludes that barriers to the use of modern opiates and synthetic opioids derived from the poppy must be addressed at an international level. The expertise of the compounding pharmacist is needed to bring drugs together in formulations previously unavailable and also in allowing novel and innovative delivery systems to be explored.

A new formulation of nasal fentanyl spray for postoperative analgesia: a pilot study.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12859464 

Self-administered intranasal meperidine for postoperative pain management.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=7788825

Pharmacokinetics and bioavailability of single-dose intranasal hydromorphone hydrochloride in healthy volunteers.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12818953

IJPC Vol 4 # 2 MARCH/APRIL 2000
Transdermal Gels in the Treatment of Diabetic Neuropathy
Author(s):Hodges, Caroline J.; Jones, Thomas H.; Willoughby, David L.
Diabetic neuropathy refers to a large number of clinical syndromes affecting both the autonomic and peripheral nervous systems and both type 1 and type 2 diabetes patients. In this article, the authors place particular emphasis on the use of ketamine Pluronic lecithin organogels for treating diabetic neuropathy. They also discuss the etiology of diabetic neuropathy, its clinical presentation, pain management (glycemic control, tricyclic antidepressants, anticonvulsants, ketamine and autonomic agents) and provide three brief case reports describing the use of a polymedicine formula . They conclude that medications administered by transdermal gels are a viable option and potentially the most rewarding for a compounding pharmacist, as they allow pain relief with fewer adverse effects. The real challenge is deciding whether the patient should begin with the polymedicine formula or with ketamine 10% and amitriptyline 2%, with additional ingredients added as needed to determine the optimal combination of medications for analgesic effects. More research is needed to determine the best combination of agents.

Phonophoresis versus topical application of ketoprofen: comparison between tissue and plasma levels.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12882611

IJPC VOL 4 # 4 JULY/AUGUST 2000
Ketamine for Pain in Hospice Patients
Author(s):Wood, Robert M.
The author has been using ketamine to treat hospice patients for several years, with varying degrees of success, and reports being most successful with the transdermal-gel form. He has also had success with ketamine administered as a nasal spray. In addition to providing general comments on the use of ketamine in this context, he presents four brief case reports demonstrating the use of ketamine and other medications in treating pain associated with various types of cancer.

A metabolic basis for fibromyalgia and its related disorders: the possible role of resistance to thyroid hormone.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12888300

Neuroendocrine perturbations in fibromyalgia and chronic fatigue syndrome. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11084955

Ultra-low doses of naltrexone or etorphine increase morphine's antinociceptive potency and attenuate tolerance/dependence in mice.
http://www.ncbi.nlm.nih.gov/pubmed/9200746?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlus

Drugs used in the treatment of opioid tolerance and physical dependence: a review.
http://www.ncbi.nlm.nih.gov/pubmed/15124977?ordinalpos=8&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum

Dextromethorphan-associated epidural patient-controlled analgesia provides better pain- and analgesics-sparing effects than dextromethorphan-associated intravenous patient-controlled analgesia after bone-malignancy resection: a randomized, placebo-controlled, double-blinded study.
http://www.ncbi.nlm.nih.gov/pubmed/14980926?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlus

Dextromethorphan Mitigates Phantom Pain in Cancer Amputees http://www.annalssurgicaloncology.org/cgi/reprint/10/3/268.pdf

A new formulation of nasal fentanyl spray for postoperative analgesia: a pilot study.
http://www.ncbi.nlm.nih.gov/pubmed/12859464?ordinalpos=4&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum

Patient-controlled intranasal analgesia: effective alternative to intravenous PCA for postoperative pain relief.
http://www.ncbi.nlm.nih.gov/pubmed/10764171?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlus

A multiple-dose phase I study of intranasal hydromorphone hydrochloride in healthy volunteers.
http://www.ncbi.nlm.nih.gov/pubmed/15502034?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum

A critical review of controlled clinical trials for peripheral neuropathic pain and complex regional pain syndromes.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=9415498

Subanesthetic ketamine infusion therapy: a retrospective analysis of a novel therapeutic approach to complex regional pain syndrome.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15367304

Analgesic effects of ketamine ointment in patients with complex regional pain syndrome type 1.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12373705

Topical ketamine gel: possible role in treating neuropathic pain.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15101968

Ketamine as an analgesic: parenteral, oral, rectal, subcutaneous, transdermal and intranasal administration.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14640353

Treatment of pain crisis at end of life from severe lower extremity venous outflow obstruction with hyperalgesia and allodynia.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14622779

A pilot study examining topical amitriptyline, ketamine, and a combination of both in the treatment of neuropathic pain.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=1296625959 

Intravenous Ketamine Infusion as an Adjuvant to Morphine in a 2-Year-Old With Severe Cancer Pain From Metastatic Neuroblastoma.
Tsui BC, Davies D, Desai S, Malherbe S.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15454842 

Ketamine as adjuvant analgesic to opioids: a quantitative and qualitative systematic review.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15271729

Safety and efficacy of intranasal ketamine for the treatment of breakthrough pain in patients with chronic pain: a randomized, double-blind, placebo-controlled, crossover study.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15109503

Equivalence study of a topical diclofenac solution (pennsaid(r)) compared with oral diclofenac in symptomatic treatment of osteoarthritis of the knee: a randomized controlled trial.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15468367

Phonophoresis versus topical application of ketoprofen: comparison between tissue and plasma levels.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12882611



Flavored PLO Gel For Oral Neuropathic Pain:
 A Case Study
Chuck Fulmer, RPh, FIACP

In April of 2001, a local pain specialist called with a problem. He had an 81-year-old female patient with neuropathathic pain radiating from the roof of the mouth to the left eye. He had rejected the idea of nerve blocks to relieve the pain due to her age. His first though was to prepare a mouthwash to relieve her pain. I explained that I did not feel that we could keep a mouthwash in contact with the oral mucus long enough to be truly effective. Upon questioning the physician, I determined that the patient wore dentures. I explained that we had previously prepared a flavored transdermal gel. I suggested that we use this gel as the vehicle for Ketamine 10%, a calcium channel blocker NMDA receptor antagonist, Gabapentin 10%, a glutamate antagonist, and Bupivacaine 2%, an anesthetic which lasts longer than Lidocaine. I explained that applying this medication under the upper denture would keep the medication in contact with the oral mucosa, allowing better penetration and pain relief.

The physician’s response was “Lets go for it”. We used a cinnamon flavored Pluronic F127 Gel combined with apple flavor to prepare a PLO of Bupivicaine 2%, Gabapentin 10% & Ketamine 10%. We used this flavor combination because we had used it successfully previously. We dispensed this in a plastic tube with instructions to apply a 1 inch (500mg) to 2 inch (1000mg) ribbon of gel to the inside of the upper denture 2 times a day. The patient was counseled about the possibility of disassociative effects from the Ketamine and cautioned her not to do anything requiring mental alertness, until she determined her response to the medication. The patient was also counseled on the possibility of rapid heartbeat due to the Bupivicaine and told to stop if it were to occur. The patient’s daughter was with her and reinforced the warning to her mother.

Later, I received a call from the patient. She stated than the 50 mile trip home was so long and the pain was so bad, that she had applied the medication in the car.

She had 90% relief of her pain by the time she arrived home. “It has surpassed anything that I imagined possible” were her words.

Several days later I received a phone call from the physician, he thanked me for the suggestion and said “you really made me look good on that one.” The following week he came into the pharmacy to thank me again, in person.

In May the patient called asking for a refill and a request to improve the flavor if we could. We had previously used the apple/cinnamon flavor for several oral transmucosal gels with good result. We made a small batch to see what we needed to do to improve the flavor. The gel smelled like a fresh baked apple pie. We figured that we would just need to tweak the flavors to get it right, however this apple pie smelling gel tasted like rocket fuel. How this woman had tolerated this taste for a month, I will never know other than the fact she had excellent pain relief.

Back to the drawing board we went and after consulting PCCA’s Flavor Guru, Lawson Kloesel, we changed the cinnamon to lemon. There was considerable improvement but it was still lacking. My technician, Sharlaine Fulmer, said lets try a small amount of salt to enhance the flavor. That did it. We had a palatable oral transmucosal PLO for neuropathic pain.

The patient was happy with the flavor and continued to have the prescription on a monthly basis. In January 2002, she complained that occasionally she had some “strange feelings after using the medication”. She stated, that when she had them, she was afraid to drive. In February 2002, I called the physician and suggested that we reduce the strength of the Ketamine. He concurred, the new formula was Bupivicaine 2%, Gabapentin 10% and Ketamine 5%. The patient stated that she had more days that the pain was not adequately controlled. The patient tried changing the quantity applied and/or the frequency of application. She still experienced some pain break through. In August 2002 the strength of the Ketamine was increased to 6%. Currently, September 2002, she is still experiencing some pain but no disassociative reactions. I feel that the Ketamine is going to have to be increased from 7% to 7.5% to control her pain without side affects.