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Hyperalgesia associated with the iontophoresis of opioids in the skin

de Silva-Rossdeutscher, Evelyn (2000) Hyperalgesia associated with the iontophoresis of opioids in the skin. PhD thesis, Murdoch University.

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Chronic pain is a part of many disorders and illnesses. Systemic treatment with opioids, although effective in controlling pain, very often produces uncomfortable side effects. Non-invasive methods of drug delivery which minimize systemic side effects are therefore important for the management of chronic pain. Iontophoresis is one such method; in the current project, the effects of iontophoresis of opioids on local pain control were investigated in 8 experimental studies on healthy volunteers.

In Study 1, the effects of morphine iontophoresis in capsaicin-inflamed skin were examined. The optimal dose of morphine iontophoresis (1, 2, 4 or 8 minutes) required to inhibit thermal and mechanical hyperalgesia evoked by radiant heat and a von Frey filament was investigated 10 and 30 minutes following the final iontophoresis. Saline was iontophoresed for the same duration as morphine and was used as the control. Unexpectedly, the iontophoresis of morphine produced significantly greater thermal hyperalgesia than saline, with the 2 minute dose producing the greatest hyperalgesia. Some indication of nonspecific effects of iontophoresis were also detected at the saline sites. Sites iontophoresed with morphine produced greater mechanical hyperalgesia than sites iontophoresed with saline when tested after 30 minutes. It was suspected that the hyperalgesia found was due to histamine release because of the blistering observed at morphine iontophoresis sites.

Study 2 was carried out to investigate the effects of pretreating 2 minute iontophoretic doses of morphine and methadone with naloxone iontophoresis. Methadone was introduced because it was reported to not release histamine. Nonspecific effects of iontophoresis were examined by introducing control sites that did not receive any iontophoresis. The specific effect of a 6.15 minute naloxone iontophoresis was also investigated on thermal and mechanical hyperalgesia using the same sensory tests as in Study 1. Heat pain thresholds were lower at the saline sites than at control sites tested 10 minutes after the final iontophoresis. There were no nonspecific effects of iontophoresis on mechanical hyperalgesia. Iontophoresis of naloxone on its own did not affect thermal or mechanical hyperalgesia. Although pretreatment of morphine and methadone sites with naloxone did not influence the heat pain threshold, pretreatment of morphine sites with naloxone produced significantly less mechanical hyperalgesia than pretreatment with saline. A similar effect was detected for methadone when sites were tested after 30 minutes. Although naloxone pretreatment resulted in slightly fewer cases of blistering, it did not altogether prevent the wheal formation resulting from morphine iontophoresis.

Study 3 was carried out to test whether a 4 minute or 30 second iontophoresis was required for methadone to produce analgesia in capsaicin-inflamed skin. Unlike morphine, methadone did not produce hyperalgesia when tested 10 minutes after the iontophoresis. Therefore since we were looking for analgesia, sensory testing was conducted 10 minutes after the final iontophoresis in this study and in all subsequent studies. A second measure of heat pain was introduced, that of suprathreshold heat pain ratings to 35°C) 40°C and 45°C held for 7 seconds on each site. In addition, mechanical pressure pain thresholds were measured using a pressure algometer in place of the von Frey hair that was used in Studies 1 and 2. As in Study 2, nonspecific effects of iontophoresis were examined at the different doses administered. Also, the effects of a 6.15 minute naloxone iontophoresis was investigated. However, in this study, an additional 4 minutes or 30 seconds of saline iontophoresis was included in order to equalize the time of iontophoresis at each site so that the specific effect of methadone iontophoresis at the two doses could be compared. Finally, the effect of pretreating the methadone sites with naloxone was compared with sites pretreated with saline iontophoresis. Nonspecific effects of iontophoresis were found for heat pain thresholds and suprathreshold ratings of heat pain, with the saline iontophoresis sites producing greater hyperalgesia to heat pain than control sites. Sites iontophoresed with naloxone produced higher heat pain thresholds than sites iontophoresed with saline, but the effect only approached significance (P=0.056). However, when ratings to 40°C were analyzed separately, naloxone produced significantly less sensitivity to heat than the saline control. This effect was not found for mechanical pressure pain thresholds but a dose effect was obtained, with the 10.15 minute iontophoresis producing significantly lower mechanical pressure pain thresholds than the 6.45 minute iontophoresis. As for the specific effects of methadone, a dose effect was obtained for mechanical pressure pain thresholds, with the longer period of iontophoresis producing greater hyperalgesia. Pretreating methadone sites with naloxone resulted in higher heat pain thresholds. A significant dose effect was also obtained for heat pain thresholds mechanical pressure pain thresholds and sensitivity to heat ratings, with greater hyperalgesia obtained from the total 10.15 minute iontophoresis than the 6.45 minute iontophoresis. Finally, when the results for heat pain thresholds from Study 2 were combined with those from this study; pretreatment of methadone sites with naloxone was found to produce significantly higher heat pain thresholds than pretreatment with saline.

Two experiments were carried out in Study 4 in skin not treated with capsaicin. The first experiment examined whether methadone induced an inflammatory reaction in the skin as a result of iontophoresis. Since the longer duration of iontophoresis produced greater hyperalgesia in Study 3 skin blood flow for a 4 minute iontophoresis was monitored. The effect of methadone iontophoresis on heat and mechanical hyperalgesia was also investigated. The 4 minute methadone iontophoresis produced significantly greater flushing than the saline and control sites, suggesting that methadone provoked the release of histamine. In the second experiment, the effect of pretreating the methadone site with naloxone was compared with pretreatment with saline on skin blood flow and sensory tests. The pressure algometer was replaced by a stronger von Frey hair to measure mechanical hyperalgesia. Although naloxone iontophoresis produced significantly greater vasodilatation than saline, pretreatment with naloxone was found to inhibit the flushing response to methadone compared to pretreatment with saline. The methadone site pretreated with saline also produced significantly lower heat pain threshold than the naloxone pretreated site. However, ratings of heat pain at 45°C produced the opposite effect, that is pretreatment with naloxone produced greater hyperalgesia than pretreatment with saline. No differences were found for mechanical ratings to punctate pressure.

Study 5 was carried out to investigate the effects of repeating a 4 minute iontophoresis in skin not treated with capsaicin. It was hypothesized that the vasodilatation resulting from the methadone iontophoresis in Study 4 was due to histamine release from mast cell degranulation. It was therefore expected that when methadone was iontophoresed for the second time, the degranulated mast cells would be depleted of histamine and other nociceptor inflammatory mediators and methadone would therefore be able to produce analgesia. Overall, methadone produced significantly greater vasodilatation than saline. After the second iontophoresis of methadone, the heat pain threshold was significantly lower at the methadone site than at the saline and control sites. This effect was also obtained for ratings of sensitivity to heat. However, this effect was not detected for sensitivity to punctate pressure.

Study 6 was also carried out in skin not treated with capsaicin. Mepyramine an antihistamine, was used to pretreat the methadone site in the hope that by blocking histamine receptors, analgesia would result from the iontophoresis of methadone. Although pretreatment with mepyramine iontophoresis resulted in higher skin blood flow than saline, nevertheless it significantly inhibited the flushing response to methadone. However, pretreatment with mepyramine did not block the heat and mechanical hyperalgesic effect of methadone. Instead, it increased mechanical hyperalgesia compared with its control site.

The final study was carried out to examine the effects of mepyramine pretreatment on a 4 minute and 30 second methadone iontophoresis in capsaicin-inflamed skin. The mepyramine pretreatment did not produce analgesic effects and neither did it inhibit thermal or mechanical hyperalgesia.

Taken together, the findings of the 8 studies indicate that although peripheral opioid effects were present, as evidenced by naloxone blocking the hyperalgesic effect of morphine and methadone, iontophoresis is not a useful method of introducing opioids into the skin to relieve pain evoked by thermal and mechanical stimuli.

Item Type: Thesis (PhD)
Murdoch Affiliation(s): Division of Social Sciences, Humanities and Education
Notes: Note to the author: If you would like to make your thesis openly available on Murdoch University Library's Research Repository, please contact: Thank you.
Supervisor(s): Drummond, Peter
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