Over a 12-month period, patients with PNDs were approximately twice as likely to have been prescribed pain-related medications by their GPs than patients without evidence of these disorders (83% vs. 43%, respectively)-most commonly, NSAIDs and opioids. Despite the proven efficacy of antidepressants (especially, TCAs) in treating neuropathic pain, which has led to recommendations regarding their use as first-line therapy [4
], only 30% of PND patients received prescriptions for these agents, and only 12% had been prescribed AEDs. These patterns of medication prescribing may indicate that UK GPs may be more comfortable with "traditional" analgesics for the treatment of neuropathic pain, which may have been appropriate to some degree, given that evidence of efficacy of opioids in neuropathic pain was available during the study period [37
]. (We also note that current treatment recommendations, which were promulgated after the end of our study period, list opioids as second- and/or third-line options for neuropathic pain [5
].) On the other hand, we were unable to ascertain the number of patients who received TCAs and AEDs in the past and discontinued these medications due to adverse effects or lack of efficacy. We also note that back pain with neuropathic involvement-the most frequently noted PND (~46% of all PND patients)-is often associated with both neuropathic and nociceptive pain; the latter often responds well to NSAIDs and/or opioids.
Patients with PNDs also had more GP encounters with diagnoses of other medical problems (e.g., digestive, circulatory, and respiratory disorders, depression, anxiety) compared with their age-and sex-matched peers without evidence of PND; they also had higher levels of use of non-pain-related medications, such as anti-ulcerants, systemic anti-infectives, and dermatologicals. Patients with PNDs averaged 10 additional GP office visits over 1 year, and twice as many specialist referrals and hospitalizations; 17% had at least one physician-excused absence from work versus as opposed to only 7.0% in the comparison group. Other studies of US and German patients have reported similar findings [7
While the precise reasons for these associations are unclear, a number of possible explanations come to mind. For one, some comorbid conditions may be etiologically related to PNDs-for example, diabetes, vascular complications thereof, and diabetic peripheral neuropathy-and such associations therefore are not unexpected. More generally, since neuropathic disorders are often chronic and difficult to treat, patients with PNDs may present more frequently to their GPs than patients without these disorders. More frequent visits may lead to more opportunistic case findings, and hence a higher rate of clinical recognition of many complaints and diseases that otherwise might have gone undiagnosed and/or untreated. Difficulties in diagnosing neuropathic disorders also may have yielded spuriously high rates of comorbid conditions among PND patients. On the other hand, since THIN does not have a direct link to hospital data and/or sick notes, our findings may actually underestimate the prevalence of various comorbidities. Further study is needed to better understand how common these comorbidities are in patients with PNDs, as well as the relationship between these conditions and PNDs.
In their study utilizing another electronic database containing information from GP encounters in the UK, Gore and colleagues reported that NSAIDs were the most commonly dispensed medication among patients with "pure" PNDs (i.e., conditions in which pain was believed to be predominantly neuropathic in nature) (53% of all identified patients with PNDs) [12
]; 17% received TCAs, 12% received AEDs, 11% received a second-generation antidepressants (e.g., SSRIs), and 9% received opioids. We generally observed much higher levels of prescribing of these medications in our study, the only exception being NSAIDs. Of particular note, the number of PND patients who were prescribed opioids was almost fivefold higher in our study than that reported by Gore and colleagues. While the precise reasons for this difference are unclear, it may be due to differences in operational definitions of study measures (e.g., how combination products containing NSAIDs and opioids were classified) and/or differences in the study databases. Another possible reason may be changes in practice and prescribing patterns that have occurred between the timeframes of the Gore et al. study (CY2001) and ours (CY2006), although the magnitude of difference seems too high to be explained by this factor alone.
Patterns of prescribing of pain-related pharmacotherapy among our study subjects also differed substantially from those reported by Hall and colleagues, who used the same database to examine patterns of pharmacotherapy among patients with post-herpetic neuralgia (N = 1923), trigeminal neuralgia (N = 1862), phantom limb pain (N = 57), and painful diabetic neuropathy (N = 1444) between May 2002 and July 2005 [11
]. Specifically, Hall et al. reported substantially higher percentages of patients receiving prescriptions for AEDs (32.5% vs. 12.1% in our current study) and TCAs (41.3% vs. 19.9%); we observed higher percentages of patients receiving prescriptions for opioids (49.5% vs. 29.1% in Hall et al.), NSAIDs (56.5% vs. 30.6% ["non-opioid analgesics"]), and other antidepressants (10.0% vs. 3.7%). The biggest reason for this discrepancy is likely the sample selected-namely, Hall et al. focused on only four PNDs, while we included several other types of PNDs (e.g., back pain with neuropathic involvement, causalgia, nerve impingement syndromes).
Our study has several limitations. Perhaps most important, our findings are based on information from CY2006. Treatment guidelines changed after CY2006 and now recommend a number of different medications as first-line therapy for PNDs (e.g., TCAs, selected AEDs, selected SNRIs, topical lidocaine) [5
]; the degree to which our findings represent current practice patterns in the UK is unknown.
Second, information on medication use was limited to drugs prescribed by GPs. Thus, to the extent that patients with PNDs (or those in the comparison group, for that matter) used medications available for direct retail purchase (i.e., without a prescription) and/or received "private prescriptions" (i.e., prescriptions wholly paid for by the patient [as opposed to the NHS), we may have underestimated total medication use.
Third, we do not know the reason(s) why particular medications were prescribed (e.g., for the treatment of PNDs or for pain associated with other conditions). Since some medications designated as "pain-related" also may be used to treat conditions that are not typically associated with pain (e.g., AEDs and seizure disorders, antidepressants and depression), it would be incorrect to infer that these agents were used exclusively for the treatment of neuropathic pain. However, only 4% of PND patients-and 3% of those in the comparison group-had any encounters at which a diagnosis of depression was recorded; corresponding values for epilepsy were 0.2% and 0.1%, respectively (data not shown). Similarly, given the widespread prevalence of comorbid pain-related conditions among patients with PNDs, as well as the possibility of "mixed" pain (i.e., neuropathic and nociceptive) among those with back pain with neuropathic involvement, it is possible that NSAIDs (and other pain-related medications for that matter) may have been prescribed for the treatment of pain that was not neuropathic in origin (e.g., triptans for migraine headache). Since we did not have access to medical records, the degree to which this actually occurred must remain conjectural.
Fourth, the study database is limited to information from GP encounters. Given the large numbers of PND patients with medical and psychiatric comorbidities-as well as the difficulty of treating PNDs-it is reasonable to expect that some patients in the study sample also had encounters with healthcare providers other than GPs.
Fifth, the GP-centric records of referrals, sick notes, and hospitalizations that are available in the study database are complete only to the extent that GPs actually record such information; to the extent that this information is not recorded by GPs, our findings may represent underestimates of healthcare utilization and prescribing patterns in this population.
Sixth, study subjects were selected based on evidence of at least one GP encounter during which a diagnosis of a PND was recorded during the one-year study period. Thus, patients who were exclusively under the care of specialists (e.g., neurologists, pain specialists) for their neuropathic pain, but who saw GPs for other reasons, would not necessarily have had GP encounters at which PNDs were noted. Not only would these patients not have been designated as having PNDs, but they also could have been selected for inclusion in the comparison group. On the other hand, the database does not contain information on how physicians rendered their diagnoses. Given that some types of PNDs are more difficult to diagnosis than others [42
], and others are not exclusively neuropathic in origin (e.g., atypical facial pain) [45
], it is possible that we may have misclassified some patients as having PNDs who in fact suffered from nociceptive pain. Unfortunately, since the database does not contain information that would shed light on these issues, the nature and extent of any misclassification that might have occurred is unknown.