The Evolving Perception of Opioids in Wound Care

Opioid: Natural, synthetic, or semi-synthetic chemicals that interact with opioid receptors on nerve cells in the body and brain and reduce the intensity of pain signals and feelings of pain.  — U.S. Centers for Disease Control and Prevention¹

In 2017, the U.S. Centers for Disease Control and Prevention reported that more than 70,000 people died from drug overdoses; of which, 67.8% of deaths involved an opioid and those between the ages of 25 and 54 comprised the highest number of fatalities.^2,3 Efforts to combat the rising death toll have been made in recent years, including the addition of medical marijuana laws. According to their 2014 study published in JAMA Internal Medicine, Bachhuber et al found that states with medical marijuana laws had a decreased rate of opioid-related deaths than states without medical marijuana laws.⁴ However, even those results have been contradicted.⁵

In this article, we will take an abbreviated look at the role opioids played in medicine from the 1800s to the mass production of OxyContin as well as their place in today’s wound care.

A Pharmaceutical Foundation

Although the development of opioids started in the 1900s, opium was the subject of much interest and study prior to that, especially in the 1800s. In 1803, German chemist Friedrich Sertürner isolated the most active ingredient in opium to develop a drug he called “morphium” for the Greek god of dreams, Morpheus.^6,7 With this new drug, Sertürner theorized its higher potency would mean less of it was needed, thus decreasing the likelihood of a person forming an addiction to morphium and even treating an opium addiction.⁸ Unfortunately, as a result of his extensive study, Sertürner fell prey to morphium addiction.^7,9 Despite Sertürner’s outspokenness regarding the devastatingly addictive side effect the drug carried, Merck Pharmaceuticals mass produced it and renamed it “morphine.”⁹

In 1849, Mrs. Winslow’s Soothing Syrup (aka, “The Baby Killer”) was first brought to market as the all-powerful cure for a teething and colicky baby. Two ingredients of the syrup were alcohol and morphine sulfate—65mg/oz of morphine, with one teaspoon equaling about 20 drops of laudanum. Exact numbers are unknown, but it is thought that thousands of infants overdosed or suffered from addiction and withdrawal due to the “soothing” syrup.¹⁰

After years of its use, chemists attempted to further “perfect” Sertürner’s work by making it non-habit forming. In 1874, Dr. Charles Romley Alder Wright created diacetylmorphine—a gray-white powder—from boiling morphine with the reactive form of acetic acid.^9,11 This creation did not lead to any further developments until decades later when chemists employed by Bayer Laboratories picked up his study.⁸

Felix Hoffmann and Heinrich Dreser, chemists at Bayer Laboratories, studied diacetylmorphine in the hopes of producing a less potent and less addictive version; however, the opposite effect came true.^8,9 Dreser confirmed Wright’s findings that diacetylmorphine is far more potent than morphine.^9,11 He tested his semi-synthetic drug on animals and humans (from workers to patients) and saw no sign of addiction after 4 weeks of observation, which only solidified his belief of it as a nonaddictive pain reliever.^8,9

In 1898, Dreser lauded this version of morphine as the “cure all” in the scientific community, declaring its ability to treat anything from the common cold to headaches to respiratory infections.^8,11 However, Dreser had no evidence-supported basis to back up his proclamations even as he continued to use it in his marketing efforts as he sold the drug.⁸ Naturally, the scientific audience applauded his profound findings and Bayer Pharmaceuticals was thrilled enough with the reception to market it under the name Bayer Heroin.¹¹

Abundantly acknowledged today, both morphine and heroin are highly addictive; thus, neither drug became the be-all, end-all, pain reliever with zero habit-forming side effects. Instead of revisiting morphine, scientists went back to opium and began study on codeine (analgesic and cough suppressant), alpha-narcotine and papaverine (muscle relaxants), and thebaine.⁹

In 1906, the American Medical Association recommended heroin for the treatment of bronchitis, pneumonia, consumption, asthma, whooping cough, laryngitis, and certain forms of hay fever—and for overall general use in the place of morphine, because it was thought to be non-habit forming.^9,12

The first opioid (ie, synthetically modified opiate) from thebaine was developed by 2 German chemists in 1916 and named “oxycodone.” Oxycodone became available in the U.S. in 1939, but not mass produced until more than a decade later.¹³ In the 1950s, oxycodone entered into the U.S. market in combination with aspirin (Percodan), ibuprofen (Combunox), or acetominphen (Percocet). But the most addictive version of oxycodone was the purest form and delivered in a time-release, known as OxyContin (Purdue Pharmaceuticals).⁷ Then, in 1995, the U.S. Food & Drug Administration approved the use of OxyContin for moderate to severe pain lasting more than a few days.^14,15

Opioids & Wound Care

Before we get into some of the evidence behind the effect of using opioids in modern wound care, it is important to note that studies have been conducted in recent years to offer alternatives to prescribing opioid analgesics. For instance, in 2018, a group of researchers conducted a quasi-experimental, cross-over pilot study to evaluate the efficacy of music therapy on pain, anxiety, and opioid use during dressing changes among burn patients.¹⁶ They found pain scores, anxiety scores, and opioid use significantly lowered during music therapy in comparison to the control (ie, no music therapy).¹⁶ Further, Hoffman and colleagues studied virtual reality as an adjunctive non-opioid analgesic in pediatrics with burn wounds.¹⁷ In total, 48 children (age range, 6-17 years) with a total body surface area burn of >10% and self-reported pain of moderate or higher “worst” pain were included.¹⁷ They found children had significantly reduced pain when using virtual reality during burn wound cleaning procedures from day 1. The authors continued to report a pattern of lower pain during virtual reality in the procedures.¹⁷

Published in 1996, Melzack and Wall theorized that a gate-control system could modulate sensory input from the skin before pain receptors could acknowledge pain perception and response. Their results were in support of their theory, showing pain can be reduced by stimulating sensory neurons, which are larger and faster than pain neurons.¹⁸

Topical applications of opioids (eg, morphine) have shown reduced pain associated with acute cutaneous wounds but impaired wound healing.^19,20 In a 2008 rat model, Rock and colleagues found topical morphine applications delayed wound closure on post-wounding days 0 to 3, but no significant delays were noted in wounds initiating treatment on day 4.¹⁹ In a systematic review, LeBon et al assessed 19 studies related to the use of topical opioids in controlling pain in palliative care settings.²⁰ Their findings showed clinical benefits in the small randomized controlled trials, but there was a deficiency of higher-quality evidence on its role.²⁰

Opioid analgesics for chronic wounds are a slightly different story but with similar findings. Farley conducted a review of the literature on cases in which patients received a topically applied opioid analgesic for chronic cutaneous lesions to assess whether the literature supported their use as safe and effective.²¹ In total, Farley reviewed more than 100 cases but data were inconsistent and irreproducible partly due to the various opioids used in the case studies. Although those reviewed studies did not provide definitive proof, they did find that applying a topical opioid that should not be absorbed into the epidermis (ie, morphine) may not adhere to the same principles when applied to a large open wound.²¹

In a 2012 study by Stein and Küchler, the authors reviewed the non-analgesic effects of opioids on wound healing and inflammation.²² From experimental studies and small-scale studies, evidence showed promising effects for topically applied analgesics to not negatively impact inflammation and wound healing and they have not shown organ toxicity.²³ However, they also acknowledge the evidence is not conclusive, and large, multicenter studies investigating different dose regimens and application intervals are necessary.²²

Perhaps the most notable study on the relationship between opioid exposure and wound healing outcomes is from a group of researchers at The George Washington University in Washington, DC.²⁴ The authors used patient data collected through the Wound Etiology and Healing study in a longitudinal cohort of 445 included patients. They discovered a strong correlation between opioid use and slower healing rates, with patients who received doses of >10mg of opioid analgesics daily healing much slower than those receiving <10mg daily or had never received them at all.²⁴ Their results are arguably the first major findings on the association between slower healing rates and increased opioid exposure.

Summary

From the days of Bayer and Merck introducing the mass production of opioids into medicine to researchers now cautioning against opioid analgesic use due to slower healing rates, opioid use is clearly still evolving. Although opioids may relieve intense pain by up to 50% in those with chronic wounds, their ability to hinder wound healing should be enough for clinicians to tread carefully with prescribing them.²² Perhaps more clinicians should seek alternate ways to relieve their patients’ pain, such as using virtual reality or music therapy.^16,17

Jaclyn Gaydos is Managing Editor of Wounds: A Compendium of Clinical Research and Practice.

 

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21. Farley P. Should topical opioid analgesics be regarded as effective and safe when applied to chronic cutaneous lesions? J Pharm Pharmacol. 2011;63:747-756.
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24. Shanmugam VK, Couch KS, McNish S, Amdur RL. Relationship between opioid treatment and rate of healing in chronic wounds. Wound Repair Regen. 2017;25(1):120-130.