In contrast to the growing body of literature on the etiology, pathophysiology, and treatment of neuropathic pain, relatively little has been reported about the clinical characteristics and costs of patients with painful neuropathic disorders (PNDs) in clinical practice, including their levels of use of pain-related pharmacotherapy and healthcare services. These issues were examined by the authors in two prior studies in which patients with PNDs were compared with an equal number of age-and sex-matched comparators [7,8]. In the first study, 55,686 patients with PNDs in the US were identified during calendar-year (CY) 2000. In the second study, 275,685 patients with PNDs who were seen by general practitioners (GPs) in Germany between 1 August 2005 and 31 July 2006 were identified. In both studies, the prevalence of various comorbidities--including fibromyalgia, osteoarthritis, and depression--was much higher in patients with PNDs, as was the use of a range of pain-related medications, including opioids, AEDs, antidepressants, and benzodiazepines. Patients with PNDs received NSAIDs and opioids to a much greater extent than one would expect if treatment guidelines relevant for the time period of either study had been followed. Lachaine and colleagues used similar methods to examine the burden of PNDs among patients in Quebec [9]. Similar to findings reported for patients in the US and Germany, patients with PNDs (n = 4912) were reported to be more likely than their age- and gender-matched comparators to have comorbidities; they also had higher levels of use of pain-related medications, such as AEDs, antidepressants, opioids, and NSAIDs [9].

There is some evidence that patients with PNDs in the UK are similarly treated. In their study of approximately 25,000 patients with post-herpetic neuralgia, trigeminal neuralgia, phantom limb pain, or painful diabetic neuropathy newly diagnosed by a GP in the UK between CY1992 and CY2002, Hall et al. reported that the medications most commonly prescribed were amitriptyline, carbamazepine, coproxamol, codydramadol, and codeine + paracetamol [10]. In a second study that also focused on patients with these four PNDs in a UK GP database between May 2002 and July 2005, Hall et al. found that the most commonly prescribed drugs included TCAs, AEDs, and opioids [11]. A study by Gore and colleagues identified 30,999 patients with PNDs in a UK GP database in CY2001 (16,690 with pain predominantly neuropathic in nature ["pure"], and 14,309 with pain likely to have both nociceptive and neuropathic components ["mixed"]) [12]. Use of medications with proven efficacy in neuropathic pain (e.g., AEDs, TCAs) was reported to be low, although levels of use were higher in patients with "pure" versus "mixed" neuropathic pain. Many PND patients also had been prescribed agents that have not typically demonstrated efficacy in neuropathic pain (e.g., NSAIDs).

Available information in the THIN database includes date of service, diagnoses (in READ format), actions taken (e.g., referrals to other providers [i.e., specialists]), and medications prescribed--including the prescribing date and the quantity prescribed. Selected demographic information is also available, including patient age and gender. All patient-level data can be arrayed chronologically to provide a detailed, longitudinal profile of all medical and pharmacy services rendered by participating GPs.

The study protocol was submitted for review to--and subsequently approved by--the UK National Health Service (NHS) Multi-Centre Research Ethics Committee (MREC).

The study sample consisted of all patients, aged ≥ 18 years, with one or more visits to GPs between 1 January 2006 and 31 December 2006 ("study period") (the most recent one-year period for which data were available at the time of study) at which a diagnosis of PND was noted (Appendix). A comparison group also was constituted, consisting of patients who did not have any GP encounters with noted diagnoses of PNDs during the same period; they were randomly selected and matched to PND patients based on age (within 1 year) and sex. (Patients in the comparison group could have other painful disorders, however, such as osteoarthritis and fibromyalgia.) All GP encounters were compiled for PND patients and patients in the comparison group over the 12-month study period.

The prevalence of selected clinically recognized comorbidities (e.g., arthritis, diseases of the circulatory system) was examined in both groups. Patients were deemed to have any of the conditions of interest if they had any encounters during the study period with a corresponding diagnosis code, or a prescription for a drug specific to that condition (e.g., diabetes was defined based on presence of corresponding [READ] diagnosis codes or prescriptions for any antidiabetic drugs).

The number of patients receiving prescriptions for pain-related and non-pain-related medications during the study period was examined. Medications were designated as "painrelated" based on their classification as analgesics or adjuvant medications in the World Health Organization's (WHO) "analgesic ladder" [13]. Although the WHO ladder was developed originally for cancer pain, the spectrum of pain-related medications also is used for the treatment of neuropathic pain [7,8,14-34]. Pain-related medications were defined to include: (1) AEDs; (2) benzodiazepines; (3) corticosteroids; (4) cyclo-oxygenase (COX)-2 inhibitors and other prescription NSAIDs; (5) muscle relaxants; (6) sedatives/hypnotics; (7) opioids (both short- and long-acting); (8) antidepressants (including TCAs, monoamine oxidase [MAO] inhibitors, and selective serotonin reuptake inhibitors [SSRIs]); (9) antimigraine agents; and (10) miscellaneous agents (injectable agents [e.g., bupivacaine], topical analgesics [e.g., lidocaine]). All other medications were designated non-pain-related.

Use of healthcare services during the 12-month study period was examined in terms of the numbers of GP visits, referrals from GPs to other healthcare providers (e.g., specialists), and hospitalizations; "sick notes" (physician-excused absences from work) also was examined. We did not attempt to attribute care specifically to the treatment of PNDs, because of inherent difficulties in attribution using electronic healthcare databases. We also did not attempt to examine nonpharmacologic treatments for PNDs, such as spinal cord stimulation and psychological support.

Mean (SD) age of patients in both groups was 56.1 (16.6) years, and 61.6% were women (Table ​(Table2).2). Nearly one-third of patients (32.9%) were ≥ 65 years of age. The prevalence of various comorbidities was higher among PND patients, including diseases of the respiratory system (33.1% vs. 24.6%, respectively), diseases of the digestive system (31.5% vs. 17.3%), diseases of the circulatory system (28.6% vs. 21.6%), depression (4.3% vs. 2.6%), and anxiety (2.8% vs. 1.7%) (all p < 0.01). Approximately one in five PND patients (i.e., 23%) had at least one encounter during the study period with a diagnosis of "symptoms, signs, and ill-defined conditions", compared with only 11.1% of patients in the comparison group (p < 0.01). Eighty-eight percent of patients with PNDs had two or more comorbidities noted by their GPs during the study period, versus 56.9% for the comparison group.

The number of patients who received prescriptions from their GPs for pain-related pharmacotherapy was approximately twice as high in the PND group than in the comparison group (82.9% vs. 43.4%,, respectively; p < 0.01), including "traditional" analgesics, such as NSAIDs and opioids, as well as "adjuvant" medications, such as AEDs, benzodiazepine, and tricyclic antidepressants (Table ​(Table3).3). The pain-related medications most commonly prescribed by GPs to patients with PNDs included NSAIDs (including COX-2 inhibitors) (56.5% of PND patients vs. 22.3% in the comparison group), opioids (49.5% vs. 13.8%), antidepressants (primarily TCAs) (29.9% vs. 9.6%), benzodiazepines (13.0% vs. 4.9%), and AEDs (12.1% vs. 0.9%) (all p < 0.01).

The number of patients receiving prescriptions for non-pain-related medications also was much higher in the PND group than in the comparison group, including general systemic anti-infectives (45.6% vs. 34.6%, respectively), ACE inhibitors (26.6% vs. 16.8%), antiulcerants (e.g., acid pump inhibitors, H2 blockers) (23.7% vs. 12.1%), dermatologicals (23.6% vs. 17.1%), and cough and cold preparations (21.1% vs. 16.4%) (all p < 0.01) (Table ​(Table4).4). Overall use of non-pain-related medications was substantially higher among PND patients versus patients in the comparison group--for example, 54.4% of the former group received prescriptions for three or more different types of non-pain-related medications during the study period, versus only 39.1% of the latter group.

Patients with PNDs averaged significantly more GP visits during the 12-month study (mean [95% CI] = 22.8 [22.6, 23.0] vs. 14.2 [14.1, 14.3] for comparison group; p < 0.01) (Table ​(Table5).5). They also had approximately twice as many referrals to specialists (2.8 [2.8, 2.9] vs. 1.4 [1.4, 1.4]) and hospitalizations (0.2 [0.2, 0.2] vs. 0.1 [0.1, 0.1]) (both p < 0.01). A total of 16.5% of PND patients had one or more "sick notes" (i.e., physician-excused work absences) during the year, versus 7.0%, of the comparison group.

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 [7,8].

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) [5,6]; 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.