The Use Of Neuropathic Pain Drugs In Patients With Sickle Cell Disease Is Associated With Older Age and Female Gender

Although neuropathic pain is becoming an increasingly recognized component of sickle cell disease (SCD) pain, national data regarding the use of neuropathic pain drugs in SCD patients do not exist. Furthermore, factors associated with the development of neuropathic pain in SCD are not well characterized. In non-SCD pain populations, neuropathic pain is associated with older age and female gender. Older age is also associated with increased thermal pain sensitivity, a marker of neuropathic pain, in both SCD patients and pain populations without SCD. Thus, the objectives of our study were to describe the use of neuropathic pain drugs in children with SCD and determine factors associated with the use of these drugs. We hypothesized older age and female gender would be associated with increased use of neuropathic pain drugs.

We used the Pediatric Health Information System (PHIS) Database (2004-09) to investigate the use of neuropathic pain drugs in SCD patients during hospital admission. The PHIS provides comprehensive inpatient data, including detailed drug information, from 43 children’s hospitals in the United States. All visits with a SCD-related (any genotype) ICD-9 discharge diagnosis (i.e., primary, secondary, tertiary) were included. To limit confounding, visits that included any psychiatric, seizure, or headache diagnosis in addition to a SCD diagnosis were excluded since neuropathic pain drugs also treat these disorders. The drugs of interest were based on published neuropathic pain treatment guidelines originally created for patients without SCD and included antiepileptics, tricyclic antidepressants, and selective serotonin reuptake inhibitors. Multivariate logistic regression analysis was used to determine the impact of age and gender on the use of neuropathic pain drugs with the outcome being whether a neuropathic pain drug was or was not prescribed during that admission. Age was classified into 4 groups (0-4, 5-10, 11-14, and 15-18 years) for clinical interpretation.

A total of 61,325 visits met inclusion criteria. Mean age was 9.8 (±5.7) years. The proportions of visits in each age group were: 0-4 (24%), 5-10 (26%), 11-14 (22%), 15-18 (28%) and 49% were female. The majority had HbSS disease (73.7%). We found 3.6% were prescribed one or more neuropathic pain drugs with the majority (3.3%) receiving one drug. There was no difference in the use of neuropathic pain drugs over time (2004-09). The most commonly used drugs were: amitriptyline (47.4%), gabapentin (27.7%), phenytoin (12.3%), and fluoxetine (11.2%) with pregabalin, venlafaxine, paroxetine, and nortriptyline used infrequently. In multivariate analysis, compared to the reference group of 0-4 years, the odds of receiving a neuropathic pain drug increased significantly and sequentially for each older age group (Table 1 

). Female patients were more likely to be taking a neuropathic pain drug [OR 1.8 (CI 1.6-1.9; p<0.0001)]. There was no significant interaction between age and gender.

Neuropathic pain drugs were infrequently prescribed (<5% of visits) which could reflect the lack of awareness of neuropathic pain in SCD during the time frame of the study. As hypothesized, older age and female gender were both significant independent predictors of neuropathic pain drug use with adolescents being almost 22 times more likely to be prescribed one of these drugs. The association between older age and neuropathic pain is supported by data in both SCD patients and non-SCD pain populations that reveal older age is associated with increased thermal pain sensitivity, a marker of neuropathic pain. This relationship suggests that SCD may have an effect on pain processing that worsens with age and also suggests that older patients have refractory pain requiring alternative drugs to opioids. Increased use of neuropathic pain drugs in females is also consistent with data in non-SCD pain populations and in SCD mice. The underlying reason for the relationship between age, gender and neuropathic pain in SCD warrants further investigation and may provide clues to the underlying neurobiology of SCD pain and help target treatment to the most at risk patients.

No relevant conflicts of interest to declare.