Pain medicine training resources: Module 5

Abstract
Many pain conditions in patients tend to co-occur, influencing the clinical expressions of each other in various ways. This paper summarizes the main concurrent pain conditions by analyzing the major interactions observed. In particular, co-occurrence will be examined in: visceral pain (especially ischemic heart disease, irritable bowel syndrome, dysmenorrhea/endometriosis and urinary pain), fibromyalgia, musculoskeletal pain and headache. Two concurrent visceral pains from internal organs sharing at least part of their central sensory projection can give rise to viscero-visceral hyperalgesia, i.e., enhancement of typical pain symptoms from both districts. Visceral pain, headache and musculoskeletal pains (myofascial pain from trigger points, joint pain) can enhance pain and hyperalgesia from fibromyalgia. Myofascial pain from trigger points can perpetuate pain symptoms from visceral pain conditions and trigger migraine attacks when located in the referred pain area from an internal organ or in cervico-facial areas, respectively. The pathophysiology of these pain associations is complex and probably multifactorial; among the possible processes underlying the mutual influence of symptoms recorded in the associations is modulation of central sensitization phenomena by nociceptive inputs from one or the other condition. A strong message in these pain syndrome co-occurrence is that effective treatment of one of the conditions can also improve symptoms from the other, thus suggesting a systematic and thorough evaluation of the pain patient for a global effective management of his/her suffering.

Abstract
Chronic pelvic pain affects both men and women; there are probably common mechanisms that involve the central nervous system. In many cases, the symptoms may be localised to a single end organ. However, the involvement of the central nervous system may result in a complex regional pain syndrome affecting the whole pelvis and as a consequence, multiple-organ symptomatology. The initial trigger may be relatively benign but a predisposed individual may develop a range of significant sensory and efferent functional abnormalities. Stimuli not normally reaching threshold may be perceived and normal sensations may be magnified to become dysphoric or painful. Problems of emptying viscera and maintaining continence may occur. Significant musculoskeletal disability may arise as well as abnormalities of the autonomic nervous system. There is an association with systemic disorders. Also, psychological, behavioural, sexual and social problems arise. In the chronic pelvic pain syndromes, treatment of the end organ has a limited role, and multidisciplinary as well as interdisciplinary management is essential.

Abstract
The fear-avoidance model is an attempt to underscore the importance of cognitive and behavioral factors, in a chain of events linking pain to disability. However, it is not clear at what time point the psychological variables within the model begin to be prominent. The aim of this study was to investigate the role of these psychological variables in the development of a chronic musculoskeletal pain problem. Three stages of chronicity, defined by duration of pain, provided a proxy for the developmental process: <1 year (N=48), 1-3 years (N=47) and >3 years (N=89). Subjects completed questionnaires on fear of movement, catastrophizing, depression, pain and function. The results indicate that the relationship between fear of movement and function is moderated by the stage of chronicity. Regression analyses showed that fear of movement did not explain any variance in the group with pain duration <1 year. Fear of movement did explain variance in the groups with pain duration of 1-3 years and >3 years. This suggests that the time point in the development of a musculoskeletal pain problem might be an essential aspect of the importance of the relationship between psychological components and function.

Abstract
Background: Women scheduled to undergo hysterectomy for benign indications frequently have preoperative pelvic pain, but it is largely unknown why pain in some cases persists or even develops after surgery. This nationwide questionnaire and database study describes pain and identifies risk factors for chronic postsurgical pain 1 yr after hysterectomy for benign indications.

Methods: A pain questionnaire was mailed to 1,299 women 1 yr after hysterectomy. The response rate was 90.3%, and the presence of persistent pain was correlated to indication for surgery, surgical procedure, type of anesthesia, and other perioperative data.

Results: Pain was reported by 31.9% 1 yr after hysterectomy (chronic pain), and 13.7% had pain more than 2 days a week. Pain was not present before surgery in 14.9% of women with chronic postsurgical pain. Risk factors for chronic pain were preoperative pelvic pain (odds ratio [OR], 3.25; 95% confidence interval [CI], 2.40-4.41), previous cesarean delivery (OR, 1.54; CI, 1.06-2.26), pain as the main indication for surgery (OR, 2.98; CI, 1.54-5.77), and pain problems elsewhere (OR, 3.19; CI, 2.29-4.44). Vaginal hysterectomy versus total abdominal hysterectomy was not significantly associated with a lower risk of chronic pain (OR, 0.70; CI, 0.46-1.06). Importantly, spinal versus general anesthesia was associated with less chronic pain (OR, 0.42; CI, 0.21-0.85).

Conclusions: Thirty-two percent had chronic pain after hysterectomy, and risk factors were comparable to those seen in other operations. Interestingly, spinal anesthesia was associated with a lower frequency of chronic pain, justifying prospective study of spinal anesthesia for patients with a high risk for development of chronic postsurgical pain.

Abstract
Background: This overview reports on interventions for pain relief and for subfertility in pre-menopausal women with clinically diagnosed endometriosis.

Objectives: The objective of this overview was to summarise the evidence from Cochrane systematic reviews on treatment options for women with pain or subfertility associated with endometriosis.

Methods: Published Cochrane systematic reviews reporting pain or fertility outcomes in women with clinically diagnosed endometriosis were eligible for inclusion in the overview. We also identified Cochrane reviews in preparation (protocols and titles) for future inclusion. The reviews, protocols and titles were identified by searching the Cochrane Database of Systematic Reviews and Archie (the Cochrane information management system) in March 2014.Pain-related outcomes of the overview were pain relief, clinical improvement or resolution and pain recurrence. Fertility-related outcomes were live birth, clinical pregnancy, ongoing pregnancy, miscarriage and adverse events.Selection of systematic reviews, data extraction and quality assessment were undertaken in duplicate. Review quality was assessed using the AMSTAR tool. The quality of the evidence for each outcome was assessed using GRADE methods. Review findings were summarised in the text and the data for each outcome were reported in 'Additional tables'.

Main results: Seventeen systematic reviews published in The Cochrane Library were included. All the reviews were high quality. The quality of the evidence for specific comparisons ranged from very low to moderate. Limitations in the evidence included risk of bias in the primary studies, inconsistency between the studies, and imprecision in effect estimates. Pain relief (14 reviews) Gonadotrophin-releasing hormone (GnRH) analogues One systematic review reported low quality evidence of an overall benefit for GnRH analogues compared with placebo or no treatment. Ovulation suppression Five systematic reviews reported on medical treatment using ovulation suppression. There was moderate quality evidence that the levonorgestrel-releasing intrauterine system (LNG-IUD) was more effective than expectant management, and very low quality evidence that danazol was more effective than placebo. There was no consistent evidence of a difference in effectiveness between oral contraceptives and goserelin, estrogen plus progestogen and placebo, or progestogens and placebo, though in all cases the relevant evidence was of low or very low quality. Non-steroidal anti-inflammatory drugs (NSAIDS)A review of NSAIDs reported inconclusive evidence of a benefit in symptom relief compared with placebo. Surgical interventions There were two reviews of surgical interventions. One reported moderate quality evidence of a benefit in pain relief following laparoscopic surgery compared to diagnostic laparoscopy only. The other reported very low quality evidence that recurrence rates of endometriomata were lower after excisional surgery than after ablative surgery. Post-surgical medical interventions Two reviews reported on post-surgical medical interventions. Neither found evidence of an effect on pain outcomes, though in both cases the evidence was of low or very low quality. Alternative medicine There were two systematic reviews of alternative medicine. One reported evidence of a benefit from auricular acupuncture compared to Chinese herbal medicine, and the other reported no evidence of a difference between Chinese herbal medicine and danazol. In both cases the evidence was of low or very low quality. Anti-TNF-α drugs One review found no evidence of a difference in effectiveness between anti-TNF-α drugs and placebo. However, the evidence was of low quality. Reviews reporting fertility outcomes (8 reviews) Medical interventions Four reviews reported on medical interventions for improving fertility in women with endometriosis. One compared three months of GnRH agonists with a control in women undergoing assisted reproduction and found very low quality evidence of an increase in clinical pregnancies in the treatment group. There was no evidence of a difference in effectiveness between the interventions in the other three reviews, which compared GnRH agonists versus antagonists, ovulation suppression versus placebo or no treatment, and pre-surgical medical therapy versus surgery alone. In all cases the evidence was of low or very low quality. Surgical interventions Three reviews reported on surgical interventions. There was moderate quality evidence that both live births or ongoing pregnancy rates and clinical pregnancy rates were higher after laparoscopic surgery than after diagnostic laparoscopy alone. There was low quality evidence of no difference in effectiveness between surgery and expectant management for endometrioma. One review found low quality evidence that excisional surgery resulted in higher clinical pregnancy rates than drainage or ablation of endometriomata. Post-surgical interventions Two reviews reported on post-surgical medical interventions. They found no evidence of an effect on clinical pregnancy rates. The evidence was of low or very low quality. Alternative medicine A review of Chinese herbal medicine in comparison with gestrinone found no evidence of a difference between the groups in clinical pregnancy rates. However, the evidence was of low quality. Adverse events Reviews of GnRH analogues and of danazol reported that the interventions were associated with higher rates of adverse effects than placebo; and depot progestagens were associated with higher rates of adverse events than other treatments. Chinese herbal medicine was associated with fewer side effects than gestrinone or danazol.Three reviews reported miscarriage as an outcome. No difference was found between surgical and diagnostic laparoscopy, between GnRH agonists and antagonists, or between aspiration of endometrioma and expectant management. However, in all cases the quality of the evidence was of low quality.

Authors' conclusions: For women with pain and endometriosis, suppression of menstrual cycles with gonadotrophin-releasing hormone (GnRH) analogues, the levonorgestrel-releasing intrauterine system (LNG-IUD) and danazol were beneficial interventions. Laparoscopic treatment of endometriosis and excision of endometriomata were also associated with improvements in pain. The evidence on NSAIDs was inconclusive. There was no evidence of benefit with post-surgical medical treatment.In women with endometriosis undergoing assisted reproduction, three months of treatment with GnRH agonist improved pregnancy rates. Excisional surgery improved spontaneous pregnancy rates in the nine to 12 months after surgery compared to ablative surgery. Laparoscopic surgery improved live birth and pregnancy rates compared to diagnostic laparoscopy alone. There was no evidence that medical treatment improved clinical pregnancy rates.Evidence on harms was scanty, but GnRH analogues, danazol and depot progestagens were associated with higher rates than other interventions.