FEATURE PA I N
Low-dose Naltrexone: A New Therapy Option for Complex Regional Pain Syndrome Type I Patients HO
O
ABSTRACT Naltrexone (an opioid antagonist) has long been used in patients overcoming alcohol and opioid dependency. However, at doses one-tenth of those commonly prescribed for the above conditions, an unexpected effect occurs that aids in alleviating pain. Although there are currently no randomized clinical trials supporting the use of lowdose naltrexone, we present a case study describing the impact of compounding lowdose naltrexone that has dramatically improved the patient’s pain symptoms which were refractory to other treatments.
OH N
O Kayla M. Sturm, PharmD Candidate Michael Collin, RPh, FIACP CASE STUDY A 17-year-old female presented to a pain specialist clinic for a secondary consult with a chief complaint of left lower extremity pain lasting over the course of three years. The pain began without a known etiology. However, a year after the pain initially started the patient sprained her ankle. Two years prior to this consult, the patient was diagnosed with Complex Regional Pain Syndrome (CRPS) Type I (CRPS-I). The physical exam found that the left-lower extremity was colder than the
right, had turned purple, and was mottled with severe allodynia. The pain was described as being primarily located in the left foot and radiated slightly above the knee in a boot distribution. The patient’s visual analog score (VAS) was 8/10. The patient’s past therapies included lumbar sympathetic blockade, physical therapy, and multiple neuroleptic medications. The patient’s current medication list included gabapentin 900 mg by mouth three times daily, ibuprofen 400 mg to 600 mg by mouth three to four times daily. Nortriptyline 10 mg by mouth at bedtime and clonidine 0.1-mg transdermal patch applied topically to the left calf once
Kayla M. Sturm is a PharmD Candidate, Class of 2016, Midwestern University-Chicago College of Pharmacy, Downers Grove, Illinois; Michael Collin is the owner of Healthway Compounding Pharmacy, Saginaw, Michigan.
www.IJPC.com
International Journal of Pharmaceutical Compounding Vol. 20 No. 3 | May | June | 2016
197
Pain
weekly were added to the patient’s therapy. At the first follow-up appointment (i.e., 9 weeks after the initial assessment), the patient reported a VAS of 7/10. Both clonidine and nortriptyline were discontinued at this appointment due to adverse drug effects of hypotension and somnolence, respectively. Trazodone was started at a dose of 50 mg by mouth at bedtime. Six weeks later at the second follow-up appointment, the patient reported a VAS of 7/10. The decision was made to begin naltrexone 1.5 mg by mouth at bedtime. At four weeks of treatment with naltrexone, the patient reported a VAS
198
of 1. The patient stated that she experienced a noticeable difference within two days of starting naltrexone therapy. She was now able to wear a regular shoe on her left foot. A 3-mg increase of naltrexone was discussed with the patient, but the patient stated that she was pleased with the results of being on 1.5 mg.
At four weeks of treatment with naltrexone, the patient reported a VAS of 1.
DISCUSSION CRPS is characterized by continuous regional pain that is either spontaneous or provoked, but the pain is disproportionate to the duration of time or severity of any known trauma. There are two subtypes of CRPS (i.e., Type I and Type II) that differ in terms of whether a major nerve lesion is present.1 CRPS Type 1 has an incidence rate of 5.46 per 100,000 people and a prevalence of 20.57 per 100,000 people. Women are four times more likely to develop CRPS than men with the upper extremities twice as likely to be affected.2
International Journal of Pharmaceutical Compounding Vol. 20 No. 3 | May | June | 2016
There have been three major proposed pathways that may cause CRPS symptoms, which include inflammatory markers, vasomotor dysfunction, and the central nervous system (CNS).3,4 In-vivo studies have shown that even with acute tissue damage, inflammation can be induced by cytokines (e.g., TNF-α, IL-1, IL-8) and nerve growth factor that stimulate the release of inflammatory neuropeptides from afferent neurons via excitation of the nociceptors. This results in the release of substance P and calcitoningene-related peptide (CGRP), therefore leading to vasodilation and protein extravasation in
www.IJPC.com
Pain
the affected tissue. Vasomotor dysfunction results in the affected limb either being slightly warmer or colder than the patient’s other limb depending upon the duration of CRPS. The warm type of CRPS typically occurs at a mean duration of four months that can progress to the cold type typically 28 months after the development of CRPS. However, approximately 20% of patients may be of the cold type from the beginning stages of CRPS. In patients that have persistent pain, structural and functional changes occur within the CNS that can eventually lead to central sensitization. This is believed to occur by spinal and trigeminal nociceptive neurons no longer being inhibited or by an increase in excitatory neuronal activity from the rostroventral medulla. Additionally, it appears that glutamate receptors are activated and upregulated leading to nociceptive neurons in the spine responding more quickly to input or potentially firing in the absence of any input. Therefore, central sensitization may cause chronic pain, hyperalgesia, and allodynia symptoms in patients with CRPS. Furthermore, patients may experience hyperalgesic priming that occurs after an initial insult triggers changes in the primary afferent nociceptors causing hyper-responsiveness to normally painless stimuli and possible plastic changes within the CNS.3 The risk factors for CRPS have not been firmly established at this time. Potential risk factors for CRPS Type I identified include female gender (particularly post-menopausal women), ankle dislocation or intra-articular fracture, or
www.IJPC.com
the fracturing of a distal radius.5 Patients can develop CRPS after an acute tissue injury (e.g., fracture, sprain, elective surgery). In the initial stages of CRPS, the affected limb may appear red, swollen, and feel warm although the limb may instantly turn cold. Patients may experience allodynia (i.e., non-painful stimuli induced pain), hyperalgesia (i.e., stimuli produce intense pain than what would normally be experienced), and/or changes in sweating, hair growth, nail growth, or muscle weakness. Movement disorders such as dystonia may be present, but this typically appears in later stages of the syndrome.1,3 The CRPS diagnosis relies particularly on a physical exam and the patient’s clinical history, radiology, and/or laboratory data although there are no labs that are currently diagnostic of the condition.6 In 2013, guidelines published by the Reflex Sympathetic Dystrophy Syndrome Association, the International Association for the Study of Pain (IASP) criteria, is used for CRPS diagnosis. Despite the IASP criteria being highly sensitive for CRPS detection, the criteria lacks specificity and has an incidence of a correct diagnosis for CRPS occurring in less than 40% of cases.1 The Budapest criteria, which builds upon the IASP criteria, was validated and found to have a higher specificity.7 The Budapest criteria for diagnosis includes: continuous pain that is disproportionate to any inciting event and must have a minimum of one symptom in three of the four following categories1:
present with multiple medications to treat their particular symptomology. Analgesics and opiates are commonly used for moderate to severe pain. If opiates are used, long-acting opioids are preferred for the primary treatment as well as an intermediate-acting opioid for breakthrough pain. Inflammation and/or edema are treated with systemic corticosteroids, nonsteroidal anti-inflammatory drugs, or immunomodulators (e.g., infliximab). Some CRPS patients may also become depressed, anxious, or present with insomnia due to the pain that can negatively impact the patient’s quality of life. Therefore, sedatives, anxiolytics,
• Sensory (hyperalgesia, allodynia) • Vasomotor (temperature asymmetry, skin color changes, skin color asymmetry) • Sudomotor/edema (edema, sweating changes, sweating asymmetry) • Motor/trophic changes [range of motion inhibited, motor dysfunction (i.e., weakness, tremor, dystonia), trophic changes (e.g., changes in hair, nail, and/or skin)]
Additionally, patients need to exhibit one symptom in two of the above-mentioned categories at the time of evaluation. Physical therapy and pharmacotherapy are the mainstays of CRPS treatment.1 The pharmacotherapy of CRPS is largely based upon treating the symptomology of the condition. It is not unlikely for a CRPS patient to
International Journal of Pharmaceutical Compounding Vol. 20 No. 3 | May | June | 2016
199
Pain
A 60-YEAR-OLD MALE PATIENT SUFFERING FROM TYPE I CRPS
and analgesic antidepressants have been prescribed for these patients. Additionally, anticonvulsants, sodium channel blockers, N-methyl-D-aspartate receptor antagonists, and α2 adrenergic agonists have been used for allodynia or hyperalgesia symptoms. Vasomotor disturbances may be treated with calcium channel blockers or sympatholytics. Nerve blockade may be used in patients with severe pain or vasomotor disturbances. Despite the plethora of medications available to CRPS Type I patients, some patients may still experience intense pain despite being on maintenance doses. However, there have been case reports published discussing the role of low-dose naltrexone (LDN), an opioid antagonist, for the treatment of CRPS in patients with severe pain refractory to other treatment modalities. Naltrexone is a pure opioid antagonist with a high affinity for mu receptors. Currently, naltrexone has U.S. Food and Drug
200
Administration-labeled indications for alcohol and opioid dependency. Typically the dosage of naltrexone for these indications is 50 mg daily.8 For the treatment of CRPS, the dosage is typically 4.5 mg daily, which is nearly one-tenth of the dosage.9 Although functionally similar to naloxone, naltrexone has a higher oral bioavailability (0.9% to 2% versus 5% to 40%) and a longer half-life (30 to 90 minutes versus 4 hours; 6-beta-naltrexol 13 hours).8,10 The possible mechanism of action in chronic pain syndromes such as CRPS is that naltrexone antagonizes toll-like receptors 4 (TLR4), which are upregulated in microglia cells in the CNS. These receptors are responsible for the release of proinflammatory cytokines such as those discussed above.4,9 One of the most common side effects in patients on naltrexone therapy is vivid dreams. In one published paper, the incidence occurred in upwards of 37% of the patients taking low-dose LDN. It is important to note that although this side effect develops quickly (i.e., within the first doses of naltrexone), the occurrence of the dreams decreases over time.9 Despite the current lack of clinical trials for LDN, case studies published within the past three years have shown that in patients whose pain was refractory to treatments as outlined above, those patients saw improvement in their symptoms with the addition of LDN. For example, in a 48-year-old male patient who sustained an injury to the right great toe receiving aqua-therapy due to a previous injury, LDN 4.5 mg daily allowed the patient to decrease the frequency of ketamine infusions to treat his CRPS symptoms from receiving them every three weeks to every six weeks. His Numeric Rating Scale (NRS) score decreased to 5/10 from an average of 8 to 10 within two months of treatment with LDN. The patient reported marked improvement and was then able to walk without a cane, his dystonic symptoms dissipated, and the patient reported having more energy. In a second case, a 12-yearold female patient diagnosed with Ehlers-Danlos Syndrome Hypermobility Type 1 repeatedly suffered from right shoulder and right ankle dislocations. A year after developing CRPS, the patient began experiencing dystonia in the upper extremities. Within three years of the onset of CRPS, the patient suffered from a partial dislocation of the right ankle and subsequently started LDN 3 mg daily and ketamine 10-mg troches as needed due to the patient reporting a NRS of 8 to 10/10. Within four weeks of LDN therapy, the dose was increased to 4.5 mg daily with adverse events reported. Despite the patient reporting a decrease of allodynia and better tolerability to touch and temperature change, the patient continued to experience dystonia. After receiving
International Journal of Pharmaceutical Compounding Vol. 20 No. 3 | May | June | 2016
botulinum toxin A injections and placement of the right lower extremity into a cast twice due to partial dislocations, the patient’s dystonia continued. Furthermore, after stabilization of the right ankle with percutaneous pins and cadaver ligaments, the patient’s dystonia resolved as well as the allodynia in conjugation with LDN therapy. Following the surgeries, the patient rarely used the ketamine troches and reported a NRS score of 3 to 4/10.4 Naltrexone is associated with few drug interactions, except for opioids and naloxegol (i.e., peripheral acting opioid antagonist for opioid-induced constipation). Monitoring considerations for naltrexone therapy includes a liver function test at baseline and periodically thereafter and assessment for suicidal ideation and/or depression. Common adverse events related to naltrexone therapy are nausea, vomiting, headache, and vivid dreams. The occurrence of vivid dreams have been reported to decrease with the duration of therapy, however, if they become bothersome, the patient should contact their physician.8,9 Compared to other available therapies for CRPS Type I that are currently recommended in the guidelines, LDN is associated with fewer side effects and drug interactions while providing symptomatic relief in patients with refractory pain. This is an area of opportunity for compounding pharmacists to provide a therapy that will help treat multiple symptoms in patients with CRPS Type I.
CONCLUSION In patients with chronic pain syndromes such as CRPS Type I, LDN may be a viable option for patients when other treatment options have been exhausted or rendered ineffective. LDN is associated with few side effects and drug interactions. Additionally, LDN provides multiple symptom relief and reduces Visual Analog Scale/Numeric Rating Scale scores.
REFERENCES 1.
2.
Harden RN, Oaklander AL, Burton AW et al. Complex Regional Pain Syndrome: Practical diagnostic and treatment guidelines. Pain Med 2013; 14(2): 180–229. Sandroni P, Benrud-Larson LM, McClelland RL et al. Complex Regional Pain Syndrome Type I: Incidence
www.IJPC.com
Pain
Rx NA LT R E XO N E 1 .5 - M G CAPSU L E For 100 Capsules Naltrexone Hydrochloride USP
0.15 g
Capsule #3
100 each
Avicel PH-105 (microcrystalline cellulose)
13.75 g
Silica gel powder (micronized)
0.6 g
EQUIPMENT
Jansen capsule machine with #3 plates Mortar and pestle Scraper and tamper Spatula Electronic Balance METHOD OF PREPARATION
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15.
Clean all work surfaces and equipment before starting the compounding procedure. Calculate the required quantity of each ingredient for the total amount to be prepared. Weigh powder and triturate well in a mortar and pestle. Set up Jansen capsule machine for #3 capsules. Choose the plates and place in the machine. Put the capsule in the machine using the capsule loader. Make sure all capsules are correctly placed in the machine after all the capsules are loaded and push the capsules down into place. Place retainer plate on capsule machine; lock into place. Pour powder onto the capsule machine after all adjustments are made and capsules are set. Dispense the powder evenly using a powder scraper. Replace the separator and gently squeeze capsule together after capsules are full and all powder has been dispensed. Flip the retainer plate over and lock capsules together by pushing on them with your thumb. Take the capsules out of the plate and wipe with a paper towel to remove any loose powder. Dispense the quantity needed. Capsules should be checked for quality by assuring that they are evenly distributed, all capsules are locked, and capsules are free of dents and cracks.
and prevalence in Olmsted County, a population-based study. Pain 2003; 103(1–2): 199–207. 3. Marinus J, Moseley GL, Birklein F et al. Clinical features and pathophysiology of Complex Regional Pain syndrome. Lancet Neurol 2011; 10(7): 637–648. 4. Chopra P, Cooper MS. Treatment of Complex Regional Pain syndrome (CRPS) using low dose naltrexone (LDN). J Neuroimmune Pharmacol 2013; 8(3): 470–476. 5. Pons T, Shipton EA, Williman J et al. Potential risk factors for the onset of Complex Regional Pain syndrome Type 1: A systematic literature review. Anesthesiol Res Pract 2015; 2015: 956539. 6. Shah A, Kirchner JS. Complex Regional Pain Syndrome. Foot Ankle Clin 2011; 16(2): 351–366. 7. Harden RN, Bruehl S, Perez RS et al. Validation of proposed diagnostic criteria (the “Budapest Criteria”) for Complex Regional Pain Syndrome. Pain 2010; 150(2): 268–274. 8. Lexi-Drugs. Naltrexone monograph. Lexicomp. [Lexicomp Website.] Available at: https://online.lexi.com. Accessed February 26, 2016. 9. Younger J, Parkitny L, McLain D. The use of low-dose naltrexone (LDN) as a novel anti-inflammatory treatment for chronic pain. Clin Rheumatol 2014; 33(4): 451–459. 10. Smith K, Hopp M, Mundin G et al. Low absolute bioavailability of oral naloxone in healthy subjects. Int J Clin Pharmacol Ther 2012; 50(5): 360–367.
Address correspondence to Michael Collin, Healthway Compounding Pharmacy, 2544 N. McLeod Drive, N, Saginaw, MI 48604. Email:
[email protected]
PACKAGING
Package desired quantity in amber vial with prescription label. LABELING
Keep out of reach of children; store at room temperature. DOSAGE DIRECTIONS
Take one capsule by mouth at bedtime.
www.IJPC.com
International Journal of Pharmaceutical Compounding Vol. 20 No. 3 | May | June | 2016
201
