1 Department of Obstetrics and Gynaecology, University of Southampton, Southampton and 2 Britannia Pharmaceuticals Limited, 4151 Brighton Road, Redhill, UK
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Abstract |
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Key words: chronic pelvic pain/lofexidine hydrochloride/women
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Introduction |
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A possible vascular basis for chronic pelvic pain has prompted the evaluation of vasoactive agents for treatment, by analogy with cerebral migraine. Intravenous dihydroergotamine was shown to ameliorate acute exacerbations of pelvic pain (Reginald et al.1987) but we hypothesized that a sympatholytic drug might reduce pain symptoms by preventing vasospasm in the utero-ovarian vascular bed and consequent release of agents with algesic and vasodilator properties such as substance P from the vascular endothelium (Stones et al.1996
).
We undertook a placebo-controlled randomized controlled trial of the orally active 2-adrenoceptor agonist lofexidine hydrochloride, which is licensed in the UK for the treatment of symptoms associated with opiate withdrawal (Cox and Alcorn, 1995
) and has previously been evaluated for the alleviation of postmenopausal hot flushes (Jones et al.1985
).
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Materials and methods |
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Protocol
Premenopausal women with an intact uterus were eligible for entry into the study if they had had chronic pelvic pain for at least 6 months; laparoscopy had excluded specific causal pathology such as endometriosis, pelvic inflammatory disease or adhesions; they were using effective contraception which was defined as an oral contraceptive pill, barrier methods, intrauterine device or sterilization, and did not have symptoms suggestive of irritable bowel syndrome. A power calculation showed a sample size of 19 in each group to be required to achieve 90% power to detect as significantly different at the 5% level the anticipated response rates of 80% and 30% in the lofexidine and placebo groups respectively. Treatment was for 8 weeks. The protocol included weekly dose increments for the first 3 weeks depending on symptomatic response from an initial dose of 200 µg twice daily to a maximum of 600 µg twice daily. The primary end point was a 50% or greater reduction in the 10 cm visual analogue scale (VAS) for pain at the end of the study. The VAS used was a simple 10 cm line without graduations and the words `no pain' at one end and `excruciating pain' at the other. Additional end points were VAS recorded in a daily diary and the subject's self-rating of her pain as worse, unchanged, somewhat relieved, considerably relieved or completely relieved.
Assignment
Women were randomized using a sealed envelope system to receive lofexidine hydrochloride or placebo.
Masking
The randomization code was held independently of the investigators at the office of Britannia Pharmaceuticals Limited and in the hospital pharmacy from which trial medication was dispensed. The investigators were blind to the randomization code until the study was complete. Placebo and active tablets were visually identical and could not be distinguished by taste. Masking was not formally tested at the end of the study.
Statistical analysis
Using SPSS (version 10, SPSS Inc.) baseline characteristics of women randomised to the two groups were compared by unpaired t-tests or, for parity, a MannWhitney U-test. Pain categories and adverse events were cross tabulated for analysis using 2 tests. The odds ratio (OR) and 95% confidence intervals (CI) for the primary end points were calculated in Review Manager 4 (Cochrane Collaboration, 1999). Daily diary VAS for pain were compared with the end-of-study summary VAS by calculating Pearson's coefficients.
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Results |
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No serious adverse effects were observed. Of the four most common adverse events, drowsiness, dizziness and dry mouth were more common in the lofexidine group, and headache and migraine were more common in the placebo group (Table III). No changes in pulse or blood pressure were observed during the study.
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Discussion |
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A positive finding was the excellent correlation between VAS completed in the daily diary and at the end of the study. This is an important observation for future research in pelvic pain: recollection of previous pain intensity is affected by the stimulus properties (Linton and Melin, 1982) and by present mood (Bryant, 1993
) so that accurate recall of the experience of chronic pain cannot be assumed and needs to be demonstrated in individual research settings. In this setting summary measures offered a satisfactory reflection of daily pain experience.
In conclusion, current animal experimental work highlighting the role of 2-adrenoceptors in antinociception may not be directly transferable to humans. Alternatively, it may be that
2-adrenoceptor agonists would show antinociceptive efficacy in human chronic pain syndromes more clearly associated with central sensitisation or neuropathy. Summary VAS for pain are appropriate end-point measures for clinical studies in this group of patients.
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Notes |
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References |
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Submitted on August 7, 2000; accepted on March 26, 2001.