Relationship between opioid treatment and rate of healing in chronic wounds

Abstract

Opioids are routinely used analgesics in patients with chronic wounds; however the impact of opioid exposure on wound healing is poorly understood. The purpose of this study was to investigate the association between opioid exposure and wound outcome in the Wound Etiology and Healing study. This longitudinal observational study was conducted on 450 subjects enrolled in the Wound Etiology and Healing biorepository. Data were collected prospectively including baseline characteristics, pain score, longitudinal opioid exposure, and total wound surface area (tWSA). Data were analyzed using static multivariate models, fixed-effects mixed models, and time to event analysis. Using fixed-effects models, opioid dose was significantly associated with tWSA after accounting for the effects of pain score and baseline co-variates (p < 0.0001). For each 1-unit increase in ln(opioid dose + 1) the ln(tWSA + 1) increased by 0.16 units (95% confidence interval 0.13-0.19, p < 0.0001). Visits where opioids were present had ln(tWSA + 1) 0.48 units larger (95% confidence interval 0.38-0.58, p < 0.0001) than visits with no opioid exposure. Using time-to-event analysis, patients who never received opioids healed faster than those who received opioids (log-rank chi-square 11.00, p = 0.0009). Using Cox regression analysis, patients with mean opioid dose ≥10 mg were significantly less likely to heal than those with no opioid (HR 0.67 [0.49-0.91], p = 0.011) after adjusting for wound size. Patients with opioid dose >0 to <10 mg had a similar hazard of not healing as those with no opioid exposure (HR 0.88 [0.65-1.19], p = 0.40). In conclusion, opioid analgesics are commonly prescribed to patients with chronic wounds; however, the data presented suggest that opioid exposure is associated with reduced likelihood of healing in patients with chronic wounds. Whether this is a causal relationship will require further study.

FIGURE 1. Study enrollment

As 450 patients were enrolled in the WE-HEAL study at the time of data analysis. The present analysis was conducted utilizing data from the 445 WE-HEAL subjects who had an open wound at the initial visit, and had more than 1 follow-up visit available for analysis.

Figure 2. Kaplan-Meier survival estimates for non-healing stratified by opioid exposure

N=401 cases with initial tWSA>0. Time to first occurrence of tWSA= 0 is modeled for those who ever (n=292) vs. never (n=109) received opioids.

Figure 3. Cox regression survival estimates for non-healing stratified by opioid dose

N=401 cases with initial tWSA >0. Time to first occurrence of tWSA= 0 is modeled, stratified by average opioid dose. There were n=109 with mean dose 0; n=127 with mean dose >0 to < 10 mg; and n=165 with mean dose ≥ 10 mg. Adjusted for baseline total wound size, pain level, lymphedema, illicit drug use, sickle cell disease.