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The Cutting Edge |

Chronic Ulcers Caused by Injection of Substances Healing Aided by Naltrexone FREE

Albert Stuart Reece, MBBS(Hons), FRCS(Ed), FRCS(Glas), FRACGP, MD
[+] Author Affiliations

Section Editor: George J. Hruza, MD

More Author Information
Arch Dermatol. 2009;145(4):375-377. doi:10.1001/archdermatol.2009.4.
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Published online

Obesity, insulin-dependent diabetes mellitus, a sedentary lifestyle, and chronic ulceration can all be complicated by refractory substance abuse. A case is presented featuring significant improvement of these parameters and others, including successful resolution of the refractory ulceration after control with naltrexone hydrochloride implants. The case is important both as a novel form of treatment for ulcer healing in drug-dependent persons, and for potential pathophysiological insights to wound healing that might be suggested by the likely mechanisms of action of naltrexone.

REPORT OF A CASE

A 54-year-old man, 174 cm tall and weighing 117 kg (body mass index, calculated as weight in kilograms divided by height in meters squared, 38.6), with poorly controlled insulin-dependent diabetes mellitus and a long history of severe polydrug abuse (including benzodiazepines, cannabis, and heroin, 1-3 g/d for a total of 33 years, currently prescribed methadone hydrochloride, 70 mg/d) presented with a 10-month history of severe open purulent sores on the backs of his hands, heels, and feet. The ulcers had not responded to numerous treatments with antibiotics, dressings, bismuth paste, bandages, or topical colloidal gels and foams. Ulcer dressings were changed daily or 3 times weekly as prescribed by the local wound clinic. His medications included insulin, atenolol, aspirin, ramipril, simvastatin, and metformin hydrochloride.

On physical examination, the patient had multiple ulcers on all 4 distal limbs. The ulcers, which were extensive and sloughing, extended to the deep dermis, occurred on the dorsum of the hands, heels, feet, and Achilles tendon. Bare tendon was not exposed. The ulcers were related to his substance injections and developed as a natural progression of “puffy hand syndrome,” in which missed injections into the veins had caused local abscesses and finally frank ulceration (Figure 1). Continued injection into the hyperemic inflamed tissue resulted in the present ulceration. He was hypertensive with a blood pressure of 161/72 mm Hg.

Place holder to copy figure label and caption
Figure 1.

Deep sloughy ulcer on the back of both hands 2 days before the first naltrexone hydrochloride implant.

Graphic Jump Location

THERAPEUTIC CHALLENGE

Chronic ulceration of the extremities is a difficult problem in unfit obese medical patients. This was intensified in our patient by poorly controlled insulin-dependent diabetes mellitus, polydrug abuse, and the chaotic lifestyle accompanying such disorders. Both medical and topical treatments and dressings had been applied for 10 months, but relentless deterioration was observed.

SOLUTION

After a preliminary period of detoxification, naltrexone implants were inserted to control the drug addiction. The patient was treated under the legal framework of the Special Access Scheme in Australia, which allows compassionate access to unlicensed drugs and therapeutic devices for patients with life-threatening conditions. Naltrexone had been used previously for a similar problem in 2005 and resulted in rapid healing of hand and foot ulcers over a 2-month period. Rapid healing of the ulcers also occurred on this occasion in response to his initial treatment with 5.6-g naltrexone hydrochloride implants (Shenzhen Civil Life Science Co, Shenzhen, China). The first series of naltrexone implants induced only partial healing. However, when the patient required a higher dose of implant to gain full control of his drug use, the ulcers rapidly healed over 13 weeks without any special further treatment (Figure 2). The second group of implants were inserted 2 weeks after the first and were the same type as the first, with the addition of a 1- to 3-month naltrexone implant from Psychological Addiction Treatment Services, Sydney, Australia. The patient's medical treatment remained unchanged. No local or topical treatment was used beyond simple wound dressings.

Place holder to copy figure label and caption
Figure 2.

Complete ulcer healing 85 and 71 days after naltrexone hydrochloride implant insertion.

Graphic Jump Location

COMMENT

Naltrexone has been used for a variety of indications within addiction medicine, including the management of dependencies (eg, alcohol, opiates,1,2 gambling, self-mutilation, and miscellaneous problems). It has also been studied in experimental animals on corneal3,4 and gastric5,6 ulcers, but to our knowledge, its application to the common and severe clinical problem of refractory chronic ulceration has not previously been described. Clearly, control of injected drug use was an important contributing factor to the rapid resolution of the ulceration in this case.

A substantial literature has described the capacity of opiates to inhibit cell growth in virtually all tissues and of naltrexone to stimulate such growth.7 Moreover, naltrexone stimulates tissue growth in the basal state, indicating that tissue growth and, presumably, stem cell replicative activity, are under tonic opioid inhibition. The inhibitory effect of opiates on tissue growth has been shown to be blocked by naltrexone, confirming that their actions occur via the well-known opioid receptors, which are found on many cell types, including stem and progenitor cells, at least of the neural lineage.

Classical8,9 literature and modern10,11 literature have described suppression of immune responses by opiates and the compensatory immune stimulation, which is suppressed by naltrexone.9 Drug-dependent patients have many causes for immune stimulation. Innate stem cell regenerative potential in such patients is likely to be depressed both by the direct inhibition of the stem and progenitor cell cycling, by immune mechanisms impeding cell growth, and by an interactive effect of the immune system on stem cell processes.1214 Because both stem cell inhibitory and immunocompromise-immunostimulation states exist in patients such as the one described herein, it is likely that wound healing is impaired. Deficits of tissue growth have been documented in various tissues, such as teeth15 and hair,16 and the present study suggests that the skin is also involved in such defects.

It is noteworthy that this study describes the second documented occasion on which such healing occurred in response to naltrexone implant therapy in this patient. On the previous occasion, multiple naltrexone implants from Go Medical in Perth, Western Australia, were used. This dramatic response was therefore not thought to be related to any particular formulation of naltrexone, but was thought to be related to the reliable delivery of the drug from a long-term sustained-release preparation.

It would seem that the repeated observations made in this case merit further trials of naltrexone therapy in challenging patients with complex clinical presentations including diabetes mellitus, obesity, medical conditions, circulatory disorders, and substance abuse and with various other conditions predisposing to chronicity of ulceration refractory to conventional treatment modalities.

ARTICLE INFORMATION

Correspondence: Albert Stuart Reece, MBBS(Hons), FRCS(Ed), FRCS(Glas), FRACGP, MD, Southcity Family Medical Centre, 39 Gladstone Rd, Highgate Hill, Queensland 4101, Australia (sreece@bigpond.net.au).

Accepted for Publication: September 25, 2008.

Financial Disclosure: None reported.

Submissions

Clinicians, residents, and fellows are invited to submit cases of challenges in management and therapeutics to this section. Cases should follow the established pattern. Manuscripts should be prepared double-spaced with right margins nonjustified. Pages should be numbered consecutively with the title page separated from the text (see Instructions for Authors [http://archderm.ama-assn.org/misc/ifora.dtl] for information about preparation of the title page). Clinical photographs, photomicrographs, and illustrations must be sharply focused and submitted as separate JPG files with each file numbered with the figure number. Material must be accompanied by the required copyright transfer statement (see authorship form [http://archderm.ama-assn.org/misc/auinst_crit.pdf]). Preliminary inquiries regarding submissions for this feature may be submitted to George J. Hruza, MD (ghruza@aol.com). Manuscripts should be submitted via our online manuscript submission and review system (http://manuscripts.archdermatol.com).

REFERENCES

Braunwald  EFauci  ASKasper  DlHauser  SLLongo  DLJameson  JL Harrison's Principles of Internal Medicine.  Vols 1 and 2. 15th ed. New York, NY: McGraw Hill; 2001
O'Brien  CP Drug addiction and drug abuse.  In: Hardman  JG, Limbird  LE, Goodman Gilman  A, eds. Goodman and Gilman's the Pharmacological Basis of Therapeutics. Vol 1. New York, NY: McGraw-Hill; 2001:621-642
Klocek  MSSassani  JWMcLaughlin  PJZagon  IS Topically applied naltrexone restores corneal reepithelialization in diabetic rats. J Ocul Pharmacol Ther 2007;23 (2) 89- 102
PubMed Link to Article
Zagon  ISSassani  JWMcLaughlin  PJ Opioid growth factor modulates corneal epithelial outgrowth in tissue culture. Am J Physiol 1995;268 (4, pt 2) R942- R950
PubMed
Nahavandi  AMani  ARHomayounfar  HAkbari  MRDehpour  AR The role of the interaction between endogenous opioids and nitric oxide in the pathophysiology of ethanol-induced gastric damage in cholestatic rats. Fundam Clin Pharmacol 2001;15 (3) 181- 187
PubMed Link to Article
Morley  JELevine  ASSilvis  SE Endogenous opiates and stress ulceration. Life Sci 1982;31 (7) 693- 699
PubMed Link to Article
Zagon  ISVerderame  MFMcLaughlin  PJ The biology of the opioid growth factor receptor (OGFr). Brain Res Brain Res Rev 2002;38 (3) 351- 376
PubMed Link to Article
Gutstein  HB Opioid analgesics.  In: Hardman  JG, Limbird  LE, eds. Goodman & Gilman's the Pharmacological Basis of Therapeutics. Vol 1. New York, NY: McGraw-Hill; 2001:569-620
McCarthy  LWetzel  MSliker  JKEisenstein  TKRogers  TJ Opioids, opioid receptors, and the immune response. Drug Alcohol Depend 2001;62 (2) 111- 123
PubMed Link to Article
Reece  AS Evidence of accelerated ageing in clinical drug addiction from immune, hepatic and metabolic biomarkers. Immun Ageing 2007;4 (1) 6
PubMed Link to Article
Reece  AS Chronic viral hepatitis is a significant contributor to the immunosenescence phenotype of parenteral drug addiction. Addict Biol 2009;14 (2) 214- 226
PubMed Link to Article
Rother  KI Diabetes treatment: bridging the divide. N Engl J Med 2007;356 (15) 1499- 1501
PubMed Link to Article
Abrous  DNKoehl  MLe Moal  M Adult neurogenesis: from precursors to network and physiology. Physiol Rev 2005;85 (2) 523- 569
PubMed Link to Article
Edelberg  JMBallard  VL Stem cell review series: regulating highly potent stem cells in aging: environmental influences on plasticity. Aging Cell 2008;7 (4) 599- 604
PubMed Link to Article
Reece  AS Dentition of addiction in Queensland: poor dental status and major contributing drugs. Aust Dent J 2007;52 (2) 144- 149
PubMed Link to Article
Reece  AS Hair graying in substance addiction. Arch Dermatol 2007;143 (1) 116- 118
PubMed Link to Article

Figures

Place holder to copy figure label and caption
Figure 1.

Deep sloughy ulcer on the back of both hands 2 days before the first naltrexone hydrochloride implant.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Complete ulcer healing 85 and 71 days after naltrexone hydrochloride implant insertion.

Graphic Jump Location

Tables

References

Braunwald  EFauci  ASKasper  DlHauser  SLLongo  DLJameson  JL Harrison's Principles of Internal Medicine.  Vols 1 and 2. 15th ed. New York, NY: McGraw Hill; 2001
O'Brien  CP Drug addiction and drug abuse.  In: Hardman  JG, Limbird  LE, Goodman Gilman  A, eds. Goodman and Gilman's the Pharmacological Basis of Therapeutics. Vol 1. New York, NY: McGraw-Hill; 2001:621-642
Klocek  MSSassani  JWMcLaughlin  PJZagon  IS Topically applied naltrexone restores corneal reepithelialization in diabetic rats. J Ocul Pharmacol Ther 2007;23 (2) 89- 102
PubMed Link to Article
Zagon  ISSassani  JWMcLaughlin  PJ Opioid growth factor modulates corneal epithelial outgrowth in tissue culture. Am J Physiol 1995;268 (4, pt 2) R942- R950
PubMed
Nahavandi  AMani  ARHomayounfar  HAkbari  MRDehpour  AR The role of the interaction between endogenous opioids and nitric oxide in the pathophysiology of ethanol-induced gastric damage in cholestatic rats. Fundam Clin Pharmacol 2001;15 (3) 181- 187
PubMed Link to Article
Morley  JELevine  ASSilvis  SE Endogenous opiates and stress ulceration. Life Sci 1982;31 (7) 693- 699
PubMed Link to Article
Zagon  ISVerderame  MFMcLaughlin  PJ The biology of the opioid growth factor receptor (OGFr). Brain Res Brain Res Rev 2002;38 (3) 351- 376
PubMed Link to Article
Gutstein  HB Opioid analgesics.  In: Hardman  JG, Limbird  LE, eds. Goodman & Gilman's the Pharmacological Basis of Therapeutics. Vol 1. New York, NY: McGraw-Hill; 2001:569-620
McCarthy  LWetzel  MSliker  JKEisenstein  TKRogers  TJ Opioids, opioid receptors, and the immune response. Drug Alcohol Depend 2001;62 (2) 111- 123
PubMed Link to Article
Reece  AS Evidence of accelerated ageing in clinical drug addiction from immune, hepatic and metabolic biomarkers. Immun Ageing 2007;4 (1) 6
PubMed Link to Article
Reece  AS Chronic viral hepatitis is a significant contributor to the immunosenescence phenotype of parenteral drug addiction. Addict Biol 2009;14 (2) 214- 226
PubMed Link to Article
Rother  KI Diabetes treatment: bridging the divide. N Engl J Med 2007;356 (15) 1499- 1501
PubMed Link to Article
Abrous  DNKoehl  MLe Moal  M Adult neurogenesis: from precursors to network and physiology. Physiol Rev 2005;85 (2) 523- 569
PubMed Link to Article
Edelberg  JMBallard  VL Stem cell review series: regulating highly potent stem cells in aging: environmental influences on plasticity. Aging Cell 2008;7 (4) 599- 604
PubMed Link to Article
Reece  AS Dentition of addiction in Queensland: poor dental status and major contributing drugs. Aust Dent J 2007;52 (2) 144- 149
PubMed Link to Article
Reece  AS Hair graying in substance addiction. Arch Dermatol 2007;143 (1) 116- 118
PubMed Link to Article

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