Maria Adele Giamberardino

A classification of chronic pain for ICD-11

Chronic pain has been recognized as pain that persists past normal healing time5 and hence lacks the acute warning function of physiological nociception.35 Usually pain is regarded as chronic when it lasts or recurs for more than 3 to 6 months.29 Chronic pain is a frequent condition, affecting an estimated 20% of people worldwide6,13,14,18 and accounting for 15% to 20% of physician visits.25,28 Chronic pain should receive greater attention as a global health priority because adequate pain treatment is a human right, and it is the duty of any health care system to provide it.4,13 The current version of the International Classification of Diseases (ICD) of the World Health Organization (WHO) includes some diagnostic codes for chronic pain conditions, but these diagnoses do not reflect the actual epidemiology of chronic pain, nor are they categorized in a systematic manner. The ICD is the preeminent tool for coding diagnoses and documenting investigations or therapeutic measures within the health care systems of many countries. In addition, ICD codes are commonly used to report target diseases and comorbidities of participants in clinical research. Consequently, the current lack of adequate coding in the ICD makes the acquisition of accurate epidemiological data related to chronic pain difficult, prevents adequate billing for health care expenses related to pain treatment, and hinders the development and implementation of new therapies.10,11,16,23,27,31,37 Responding to these shortcomings, the International Association for the Study of Pain (IASP) contacted the WHO and established a Task Force for the Classification of Chronic Pain. The IASP Task Force, which comprises pain experts from across the globe,19 has developed a new and pragmatic classification of chronic pain for the upcoming 11th revision of the ICD. The goal is to create a classification system that is applicable in primary care and in clinical settings for specialized pain management. A major challenge in this process was finding a rational principle of classification that suits the different types of chronic pain and fits into the general ICD-11 framework. Pain categories are variably defined based on the perceived location (headache), etiology (cancer pain), or the primarily affected anatomical system (neuropathic pain). Some diagnoses of pain defy these classification principles (fibromyalgia). This problem is not unique to the classification of pain, but exists throughout the ICD. The IASP Task Force decided to give first priority to pain etiology, followed by underlying pathophysiological mechanisms, and finally the body site. Developing this multilayered classification was greatly facilitated by a novel principle of assigning diagnostic codes in ICD-11, termed “multiple parenting.” Multiple parenting allows the same diagnosis to be subsumed under more than 1 category (for a glossary of ICD terms refer to Table ​Table1).1). Each diagnosis retains 1 category as primary parent, but is cross-referenced to other categories that function as secondary parents. Table 1 Glossary of ICD-11 terms. The new ICD category for “Chronic Pain” comprises the most common clinically relevant disorders. These disorders were divided into 7 groups (Fig. ​(Fig.1):1): (1) chronic primary pain, (2) chronic cancer pain, (3) chronic posttraumatic and postsurgical pain, (4) chronic neuropathic pain, (5) chronic headache and orofacial pain, (6) chronic visceral pain, and (7) chronic musculoskeletal pain. Experts assigned to each group are responsible for the definition of diagnostic criteria and the selection of the diagnoses to be included under these subcategories of chronic pain. Thanks to Bedirhan Ustun and Robert Jakob of the WHO, these pain diagnoses are now integrated in the beta version of ICD-11 (http://id.who.int/icd/entity/1581976053). The Task Force is generating content models for single entities to describe their clinical characteristics. After peer review overseen by the WHO Steering Committee,39 the classification of chronic pain will be voted into action by the World Health Assembly in 2017. Figure 1 Organizational chart of Task Force, IASP, and WHO interactions. The IASP Task Force was created by the IASP council and its scope defined in direct consultation of the chairs (R.D.T. and W.R.) with WHO representatives in 2012. The Task Force reports to ... 2. Classification of chronic pain Chronic pain was defined as persistent or recurrent pain lasting longer than 3 months. This definition according to pain duration has the advantage that it is clear and operationalized. Optional specifiers for each diagnosis record evidence of psychosocial factors and the severity of the pain. Pain severity can be graded based on pain intensity, pain-related distress, and functional impairment. 2.1. Chronic primary pain Chronic primary pain is pain in 1 or more anatomic regions that persists or recurs for longer than 3 months and is associated with significant emotional distress or significant functional disability (interference with activities of daily life and participation in social roles) and that cannot be better explained by another chronic pain condition. This is a new phenomenological definition, created because the etiology is unknown for many forms of chronic pain. Common conditions such as, eg, back pain that is neither identified as musculoskeletal or neuropathic pain, chronic widespread pain, fibromyalgia, and irritable bowel syndrome will be found in this section and biological findings contributing to the pain problem may or may not be present. The term “primary pain” was chosen in close liaison with the ICD-11 revision committee, who felt this was the most widely acceptable term, in particular, from a nonspecialist perspective.

Pain threshold variations in somatic wall tissues as a function of menstrual cycle, segmental site and tissue depth in non-dysmenorrheic women, dysmenorrheic women and men.

Abstract Pain symptoms of many disorders are reported to vary with menstrual stage. This study investigated how pain thresholds to electrical stimulation of the skin, subcutis and muscle tissue varied with menstrual stage in normal women and compared these variations with those in women with dysmenorrhea and in healthy men at matched intervals. Thresholds of the three tissues were measured four times during the course of one menstrual cycle at four sites. Two of the sites were on the abdomen within the uterine viscerotome (abdomen‐rectus abdominis, left and right) and two were outside it on the limbs (leg‐quadriceps, arm‐deltoid). Calculated from the beginning of menstruation (day 0), the menstrual phases studied were menstrual (days 2–6), periovulatory (days 12–16), luteal (days 17–22) and premenstrual (days 25–28). Spontaneous pain associated with menstruation was measured from diary estimates on a VAS scale. Menstrual phase, dysmenorrhea and tissue: Whereas the highest thresholds always occurred in the luteal phase regardless of segmental site or stimulus depth, the lowest thresholds occurred in the periovulatory stage for skin, whereas those for muscle/subcutis occurred perimenstrually. Dysmenorrhea accentuated the impact of menstrual phase. For non‐dysmenorrheic women menstrual trends were significant only in abdominal muscle and subcutis, but for dysmenorrheic women the trends were also significant in abdominal skin and in limb muscle and subcutis. Dysmenorrhea also lowered thresholds mainly in muscle and sometimes in subcutis, but never in skin, with the greatest hyperalgesic effects in left abdominis muscle. Segmental site: Abdominal sites were more vulnerable to menstrual influences than limb sites. Muscle thresholds, but not skin or subcutis thresholds, were significantly lower in abdomen than in limbs, particularly in dysmenorrheic women. The amount of abdominal muscle hyperalgesia correlated significantly with the amount of spontaneous menstrual pain. Sex differences: Only minor sex differences were observed for pain thresholds of the arm and leg, but there was a unanimous refusal by men, but not by women, to be tested at abdominal sites. These results indicate that menstrual phase, dysmenorrhea status, segmental site, tissue depth and sex all have unique interacting effects on pain thresholds, thus adding more items to the lengthy and still‐growing list of biological factors that enter into an individuals judgment of whether or not a stimulus is painful.

Recent and forgotten aspects of visceral pain

Progress in the field of visceral pain research has been particularly rapid in recent years. Some aspects of the symptom that had previously been neglected for some time have now received a great deal of attention in both clinical and experimental studies. This regards, in particular, phenomena of hyperalgesia: (a) of visceral structures, because of local inflammatory/sensitizing processes (visceral hyperalgesia); (b) of areas of referred pain from viscera (referred somatic hyperalgesia from viscera); and (c) of a visceral structure, because of an algogenic process of another visceral domain (viscero‐visceral hyperalgesia). Clinical studies in patients have led to characterisation of subjective and objective symptoms of these phenomena. A number of studies in human volunteers (employing experimental procedures to stimulate and measure pain reactivity in both visceral structures and somatic areas of referral) have further increased the knowledge about modalities of generation of the various forms of hyperalgesia.

Reaction conditions affecting the relationship between thiobarbituric acid reactivity and lipid peroxidesin human plasma

The thiobarbituric acid (TBA) reactivity of human plasma was studied to evaluate its adequacy in quantifying lipid peroxidation as an index of systemic oxidative stress. Two spectrophotometric TBA tests based on the use of either phosphoric acid (pH 2.0, method A) or trichloroacetic plus hydrochloric acid (pH 0.9, method B) were employed with and without sodium sulfate (SS) to inhibit sialic acid (SA) reactivity with TBA. To correct for background absorption, the absorbance values at 572 nm were subtracted from those at 532 nm, which represent the absorption maximum of the TBA:MDA adduct. Method B gave values of TBA-reactive substances (TBARS) 2-fold higher than those detected with method A. SS lowered TBARS by about 50% with both methods, indicating a significant involvement of SA in plasma TBA reactivity. Standard SA, at a physiologically relevant concentration of 1.5 mM, reacted with TBA, creating interference problems, which were substantially eliminated by SS plus correction for background absorbance. When method B was carried out in the lipid and protein fraction of plasma, SS inhibited by 65% TBARS formation only in the latter. Protein TBARS may be largely ascribed to SA-containing glycoproteins and, to a minor extent, protein-bound MDA. Indeed, EDTA did not affect protein TBARS assessed in the presence of SS. TBA reactivity of whole plasma and of its lipid fraction was instead inhibited by EDTA, suggesting that lipoperoxides (and possibly monofunctional lipoperoxidation aldehydes) are involved as MDA precursors in the TBA test. Pretreatment of plasma with KI, a specific reductant of hydroperoxides, decreased TBARS by about 27%. Moreover, aspirin administration to humans to inhibit prostaglandin endoperoxide generation reduced plasma TBARS by 40%. In conclusion, reaction conditions affect the relationship between TBA reactivity and lipid peroxidation in human plasma. After correction for the interfering effects of SA in the TBA test, 40% of plasma TBARS appears related to in vivo generated prostaglandin endoperoxides and only about 60% to lipoperoxidation products. Thus, the TBA test is not totally specific to oxidant-driven lipid peroxidation in human plasma.

Artificial ureteral calculosis in rats: behavioural characterization of visceral pain episodes and their relationship with referred lumbar muscle hyperalgesia

&NA; In a rat model of artificial ureteral calculosis, the aim of the study was to characterize the behavioural manifestations of direct visceral pain and to evaluate the relationship between number, duration and complexity of the visceral episodes and the extent of referred lumbar muscular hyperalgesia. As evidenced by non‐stop video‐tape recordings over 4–14 days, almost 98% of stone‐implanted rats showed episodes similar to the writhing behaviour characteristic of noxious visceral stimulation in animals. From one rat to another, these episodes varied from very few (1–3) to a very high number (± 60), lasted a few minutes to over 45 min and were of variable complexity, as evaluated via an arbitrary scale on the basis of the combination of movements. Their number and duration decreased significantly, in a linear fashion, as time passed after the operation, so that they were mostly concentrated during the first 3 days. Number, duration and complexity of episodes were reduced by chronic treatment with morphine in a dose‐dependent fashion. Stone‐implanted rats displaying visceral episodes also showed hyperalgesia of the ipsilateral oblique musculature, as evidenced by a decrease in the vocalization threshold to electrical muscle stimulation, which was maximum on the first 3–4 days after implantation but lasted up to 10 days. The visceral episodes and the muscle hyperalgesia showed a strict relationship of interdependence: a significant, direct linear correlation was found between number and duration of episodes and degree of ipsilateral muscle hyperalgesia; such a correlation was also found between degree of complexity of episodes and tendency to also develop a contralateral muscle hyperalgesia. By applying the results of the study to the interpretation of human pathology, referred lumbar muscle hyperalgesia from ureteral calculosis would appear to be a strict function of the colic pain experienced.

Relationship between musculoskeletal symptoms and blood markers of oxidative stress in patients with chronic fatigue syndrome.

In 21 patients with chronic fatigue syndrome (CFS) versus 20 normal subjects, we investigated the oxidant/antioxidant balance and its correlation with muscle symptoms. Patients versus controls showed significantly: lower Lag Phase and Vitamin E (Vit E) concentrations in plasma and low-density lipoproteins (LDL), higher LDL thiobarbituric acid reactive substances (TBARS), higher fatigue and lower muscle pain thresholds to electrical stimulation. A significant direct linear correlation was found between fatigue and TBARS, thresholds and Lag Phase, thresholds and Vit E in plasma and LDL. A significant inverse linear correlation was found between fatigue and Lag Phase, fatigue and Vit E, thresholds and TBARS. Increased oxidative stress and decreased antioxidant defenses are related to the extent of symptomatology in CFS, suggesting that antioxidant supplementation might relieve muscle symptoms in the syndrome.

Viscero-visceral hyperalgesia: characterization in different clinical models.

&NA; Co‐existing algogenic conditions in two internal organs in the same patient may mutually enhance pain symptoms (viscero‐visceral hyperalgesia). The present study assessed this phenomenon in different models of visceral interaction. In a prospective evaluation, patients with: (a) coronary artery disease (CAD) + gallstone (Gs) (common sensory projection: T5); (b) irritable bowel syndrome (IBS) + dysmenorrhea (Dys) (T10‐L1); (c) dysmenorrhea/endometriosis + urinary calculosis (Cal)(T10‐L1); and (d) gallstone + left urinary calculosis (Gs + LCal) (unknown common projection) were compared with patients with CAD, Gs, IBS, Dys or Cal only, for spontaneous symptoms (number/intensity of pain episodes) over comparable time periods and for referred symptoms (muscle hyperalgesia; pressure/electrical pain thresholds) from each visceral location. In patients’ subgroups, symptoms were also re‐assessed after treatment of each condition or after no treatment. (a) CAD + Gs presented more numerous/intense angina/biliary episodes and more referred muscle chest/abdominal hyperalgesia than CAD or Gs; cardiac revascularization or cholecystectomy also reduced biliary or cardiac symptoms, respectively (0.001 < p < 0.05). (b) IBS + Dys had more intestinal/menstrual pain and abdomino/pelvic muscle hyperalgesia than IBS or Dys; hormonal dysmenorrhea treatment also reduced IBS symptoms; IBS dietary treatment also improved dysmenorrhea (0.001 < p < 0.05) while no treatment of either conditions resulted in no improvement in time of symptoms from both. (c) Cal + Dys had more urinary/menstrual pain and referred lumbar/abdominal hyperalgesia than Cal or Dys; hormonal dysmenorrhea treatment/laser treatment for endometriosis also improved urinary symptoms; lithotripsy for urinary stone also reduced menstrual symptoms (0.001 < p < 0.05). (d) In Gs + LCal, cholecystectomy or urinary lithotripsy did not improve urinary or biliary symptoms, respectively. Mechanisms of viscero‐visceral hyperalgesia between organs with documented partially common sensory projection probably involve sensitization of viscero‐viscero‐somatic convergent neurons.

Influence of endometriosis on pain behaviors and muscle hyperalgesia induced by a ureteral calculosis in female rats.

&NA; Endometriosis and urinary calculosis can co‐occur. Clinical studies have shown that both painful and non‐painful endometriosis in women are associated with enhanced pain and referred muscle hyperalgesia from urinary calculosis, but the mechanisms underlying this phenomenon are still poorly understood. The aim of this study was to develop an animal model adequate to explore this viscero‐visceral interaction in standardized conditions. Using a model of endometriosis previously developed to study reduced fertility and vaginal hyperalgesia, endometriosis (endo) or sham‐endometriosis (sham‐endo) was induced in rats by autotransplantation of small pieces of uterus (or, for sham‐endo, fat) on cascade mesenteric arteries, ovary, and abdominal wall. After the endometrial, but not the fat autografts had produced fluid‐filled cysts (3 weeks), urinary calculosis was induced by implanting an artificial stone into one ureter. Pain behaviors were monitored by continuous 24‐h videotape recordings before and after stone implantation. Referred muscle hyperalgesia was assessed by measuring vocalization thresholds to electrical stimulation of the oblique musculature (L1 dermatome). The data were compared with previously reported data from rats that had received only the stone. Neither endo nor sham‐endo alone induced pain behaviors. Following stone implantation, in endo rats compared to sham‐endo and stone‐only rats, pain behaviors specifically associated with urinary calculosis were significantly increased and new pain behaviors specifically associated with uterine pathology became evident. Muscle hyperalgesia was also significantly increased. To explore the relationship between the amount of endometriosis and that of ureteral pain behavior, two separate groups of endo rats were treated with either a standard non‐steroidal anti‐inflammatory drugs (ketoprofen) or placebo from the 12th to the 18th day after endometriosis induction. The stone was implanted on the 21st day. Ketoprofen treatment compared to placebo significantly reduced the size of the cysts and both ureteral and uterine pain behaviors post‐stone implantation. The size of the cysts showed a significant linear correlation with the post‐stone ureteral pain behaviors. In conclusion, endo increased pain crises and muscle hyperalgesia typically induced by a ureteral calculosis, and the ureteral calculosis revealed additional pain behaviors typically induced by uterine pathophysiology; and this enhancement was a function of the degree of endometriosis. This result closely reproduces the condition observed in humans and could be due to a phenomenon of ‘viscero‐visceral’ hyperalgesia, in which increased input from the cyst implantation sites to common spinal cord segments (T10‐L1) facilitates the central effect of input from the urinary tract.

Uterine inflammation as a noxious visceral stimulus: behavioral characterization in the rat

We have developed a model of uterine inflammation in the rat. The purpose of this study was to characterize the behavioral manifestations of uterine pain. Mustard oil was injected into one uterine horn to produce chemical inflammation. Control rats were sham-operated. Non-stop videotape recording was performed for 7 days to monitor rat behavior. Rats with uterine inflammation showed abnormal behavior during the first 4 days (hunching, hump-backed position, licking of the lower abdomen, repeated waves of contraction of the ipsilateral oblique musculature with inward turning of the ipsilateral hindlimb, stretching, squashing of the lower abdomen against the floor) suggestive of visceral pain and evidence of flank muscle hyperalgesia over 7 days indicative of referred visceral pain. This model resembles closely a state of inflammatory uterine pain and will allow to gain further insight into the neural processes which contribute to visceral nociception.

Effects of treatment of peripheral pain generators in fibromyalgia patients

Fibromyalgia syndrome (FS) frequently co‐occurs with regional pain disorders. This study evaluated how these disorders contribute to FS, by assessing effects of local active vs placebo treatment of muscle/joint pain sources on FS symptoms.