Utilization of analgesics in the multicenter study of hydroxyurea in sickle cell anemia: Effect of sex, age, and geographical location
Authors: Samir K. Ballas, Robert L. Bauserman, William F. McCarthy, Oswaldo L. Castro, Wally R. Smith, Myron A. Waclawiw
Journal: American Journal of Hematology (2010)

Several factors affect the severity and duration of sickle cell pain and its response to treatment with analgesics [1, 2]. Sex has been one of the factors reported to influence the pain experience and the response to therapy [3]. Several chronic pain disorders, such as fibromyalgia, occur more frequently in females than in males [4, 5]. Moreover, women seem to be more sensitive to painful stimuli than men [6]. However, whether differences in analgesic use by sex occur in patients with sickle cell anemia (SS) is unknown. Age also has been related to pain experience in many studies [7-9]. Moreover, we and others recently found an effect of geographic location and climatic conditions on frequency and severity of sickle cell pain [10, 11]. Studies at single sites and anecdotal reports showed that climatic conditions, especially temperature can precipitate or exacerbate pain in sickle cell disease [12-14]. However, to the best of our knowledge, there are no multicenter, randomized, and placebo-controlled studies that relate all of these factors to pain management in sickle cell disease (SCD). The Multicenter Study of Hydroxyurea (MSH) in SS [15] gave us an opportunity to report on these aspects of sickle cell pain. The hallmark of SS is the acute painful crisis. About 95% of hospital admissions of adult patients with SCD are for the treatment of the acute painful crisis [16]. The acute painful crisis is often complicated by acute chest syndrome, acute multiorgan failure, and sudden death [17-19]. Prevention of the acute painful crises is a major goal of the management of patients with SCD. This study focused on the effects of sex, age, and geographic location on the painful crisis in patients with SS who were enrolled in the MSH in SS [15]. Several recent studies about pain, in general, showed that there are major differences between males and females in processing painful stimuli and the perception of pain severity [3, 6]. Women are at a greater risk for having several types of chronic pain syndromes and they exhibit greater sensitivity to noxious stimuli than men. They also complain of pain more often than men and in more regions of the body. The prevalence of many chronic pain conditions is sex and age dependent. Moreover, women seem to deal with pain better than men do and adopt better coping strategies with pain. This may be due, at least in part, to their frequent encounter with various types of pain during menstruation, dysmenorrhea, pregnancy, labor, and delivery. Sex differences also exist in responses to opioid medications. These differences seem to pertain to the number of μ-opioid receptors in different areas of the brain. Loyd et al. [20] reported that male rats have more μ-opioid receptor expression in the periaquedutctal gray area of the midbrain compared with female rats. This area of the brain contains a large number of neurons that express μ receptors on their surface. These receptors, in turn, bind morphine and other μ-opioid agonists resulting in inhibition of transmission of the pain signal. This sequence of events suggests that μ-opioid agonists such as morphine are less effective analgesics in females than males. Some but not all clinical studies support this hypothesis [20-22]. κ-Opioid receptors, on the other hand, seem to have more density in the brain of females compared to males [23-25]. Women taking κ-opioid agonists, such as nalbuphine, have significantly greater postoperative analgesia than men [23-27]. Sex differences in response to nonopioid analgesics are equally discrepant with one study showing that only men had significant analgesic effect from ibuprofen in a study of experimental electrically induced pain [28]. Unfortunately, most of these studies were not performed in multicenter, randomized, and controlled trials. Most were single institution studies treating different kinds of pain (dental, thermal, chemical, electrical, etc.) in either ambulatory subjects or in postoperative pain. Ageing is another important factor that affects pain management especially in the elderly. Aging affects the phararmacokinetics and pharmacodynamics of medications [29]. With ageing body composition (fat/muscle ratio), gastrointestinal motility, hepatic metabolism, renal clearance, and protein binding all decrease, whereas central nervous system sensitivity to medications and their side effects increases [30]. Consequently, older patients require smaller doses of analgesics to achieve adequate pain relief. Although patients with SCD usually do not live as long as the general population, age should be considered in the planning of their pain management. Moreover, organ damage complicates SS, and by the age 40 years, many patients with SCD have evidence of variable degrees of organ damage which, in turn, will affect the metabolism of the medications taken by the patients. Our data show that the average dose of opioids, expressed in morphine equivalents, required to achieve pain relief is always significantly higher in males irrespective of the place of treatment (Table I). This may be due to a number of possibilities. The pain experienced by males may be more severe in nature or males may use opioids only when their pain is "very" severe. Women, on the other hand, may seek treatment when their pain is relatively milder compared with men. Whether the difference is due to the number of μ-opioid receptors in the brain described above or not is not clear. If males have more receptors one would expect smaller doses of opioids to achieve relief. Binding to receptors, however, is not enough unless it is followed by activation of these receptors. It is the activation of the receptors with consequent membrane hyperpolarizaion that inhibits the transmission of pain signals. Whether this is the situation in males or not awaits further studies. Another interesting finding of our study is the effect of age on the frequency of opioid utilization and their dosing (Table II). Age was expressed in four quartiles; quartile 1: 18–24 years, quartile 2: 25–29 years, quartile 3: 30–35 years, and quartile 4: more than 36 years. The frequency of utilization of opioids and their dosing at home followed a consistent pattern: the numbers were significantly lowest in quartile 1, reached a significant maximum in quartile 3, and then declined significantly in quartile 4. This pattern was significant in males only and marginally significant in females with regards to the frequency of analgesic use in at-home diaries. This sequence of events suggests that as the patients get older they become tolerant to opioids and, hence, require higher and more frequent dosing to achieve pain relief at home by age 35 years. After age 36 years, the alteration in the pharmacodynamics and pharmacokinetics described above seems to set in thus increasing the sensitivity to opioids. This sequential pattern of opioid escalation with age, however, was not found when patients were treated in acute care facilities or in the hospital. Thus, there were no significant differences among age quartiles in the frequency of opioid utilization, with the exception of oral opioid use during acute care crises in women where the pattern was reversed, with patients in quartile one using oral opioids more frequently than those in older quartiles (P < 0.0001). Similarly, the equianalgesic dosing of opioids during acute care crises and during hospitalization did not significantly differ across the four age quartiles. This suggests that when pain is severe the effect of age diminishes, or even is reversed. The inflammation that accompanies severe painful crises is associated with the release of cytokines, chemokines, acute phase reactants, and other inflammatory mediators that bind opioids and decrease their availability to bind to and activate opioid receptors. Moreover, the psychological impact of severe pain on younger patients with resultant catastrophizing may be a contributory factor. Unlike opioids, the frequency of utilization of non-steroidal anti-inflammatory drugs (NSAIDS) is significantly higher in younger patients of both sexes when treated in acute care facilities but only marginally significant in younger women during hospitalization. The third goal of this study was to examine the patterns of utilization of analgesics across different regions in the United States. The frequency of utilization of opioids and the dosing of opioids differed considerably among the four regions: Northeast, Midwest, South, and West. There was no simple and consistent pattern across all regions in these parameters of opioid utilization. Notable significant or marginally significant observations included the following. The frequency of utilization of oral opioids at home was significantly highest in the Northeast and lowest in the West with the Midwest and South in between (Table II). The frequency of utilization of parenteral opioids in acute care facilities was highest in the West and lowest in the Midwest whereas the frequency of utilization of oral opioids in acute care facilities was higher in the Midwest than in the Northeast for females but higher in both the Midwest and West when compared to the Northeast for males (Table III). This pattern suggests that the choice of the route of opioid administration is region dependent. The average daily dose of opioids also differed considerably among geographic regions with a few observations worth noting. For both males and females, the average daily dose of parenteral and oral opioids used in acute care facilities and in the hospital was highest in the Northeast and lowest in the South. However, the average daily oral opioid dose at home was highest in the South. Interestingly, the use of NSAIDS during both acute care and in-patient crises tended to be higher in the South. Thus, it seems that in the South, the trend has been to treat crises at home aggressively with oral opioids and to use NSAIDS more frequently during acute care and in-patient crises, resulting in decreased utilization of parenteral opioids in acute care facilities and in the hospital. The number and duration of in-patient painful crises were also age, sex and region dependent. The number of crises was highest in the Northeast and lowest in the South. The average duration of a painful crisis was also highest in the Northeast but lowest in the West. In summary, this study shows that management of acute sickle cell painful episodes at home, in acute care facilities, and in the hospital seems to be sex, age, and geographic region dependent. Further studies are needed to confirm these findings. Recommendations and guidelines to treat acute painful crises should take age, sex, and region into consideration. Additional Supporting Information may be found in the online version of this article. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. Samir K. Ballas*, Robert L. Bauserman , William F. McCarthy , Oswaldo L. Castro , Wally R. Smith?, Myron A. Waclawiw?, * Cardeza Foundation for Hematologic Research, Department of Medicine, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, Maryland Medical Research Institute, Baltimore, Maryland, Howard University, Department of Medicine/Hematology, Washington, DC, ? Virginia Commonwealth University, Internal Medicine - Quality Health Care, Richmond, Virginia, ? National Heart, Lung and Blood Institute, Bethesda, Maryland.