Pregabalin was most commonly prescribed for the treatment of pain in PHN (30.5%) and fibromyalgia (18.4%) in Taiwan, and this was also reflected by a high proportion of concomitant prescription of other analgesics (Table 1). Most of the prescriptions were limited to short-term use, as evidenced by a mean duration of prescription lasting 149.5 ± 299.8 days (median 28, interquartile range [IQR] 14–118), especially in PNH (89.4 ± 224.1 days) and fibromyalgia (150.8 ± 302.8 days). Besides, the mean dose prescribed was 140.7 ± 92.8 mg, which was lower than the doses used in clinical trials for NeP (3) and fibromyalgia (8), although the mean dose of prescriptions for epilepsy could be within the lower range of recommended doses (10).
The finding that pregabalin prescriptions were typically of short duration is in keeping with prior reports. According to a retrospective administrative claims data analysis from the United States, only 56.9% of patients initiating pregabalin for PHN obtained a refill during the one-year follow-up period (15). Similarly, 34% had just one single dispensed prescription for various indications, including epilepsy, generalized anxiety disorder, and neuropathic pain, indicating only 64% had further refills after the first prescription in Sweden (16). Besides, according to an Israeli study in fibromyalgia, the median time to discontinuation for antiepileptics, namely pregabalin and gabapentin, was 30 days (IQR 30–106 days) (17), and the mean prescription duration of pregabalin for pain was 52.2 days in a Japanese real-word study (18). In the present study, the persistence rates were 29.3% and 12.1% at 90 days and one year, respectively, indicating only a minority of patients continued to use pregabalin. All the above findings indicate that pregabalin prescriptions are usually discontinued early, which is a universal phenomenon.
A number of factors could be responsible for the short duration of pregabalin treatment for pain. As the NeP in PHN could resolve in months or years (19, 20), treatment would be no longer necessary after resolution of symptoms. More importantly, pregabalin could be prescribed off-label for the acute pain in herpes zoster rather than for PHN in some patients in the present cohort. In fact, 5.8% of pregabalin users were prescribed with anti-viral agents at the same time (Table 1), and concomitant use of anti-viral agents was associated with decreased likelihood of pregabalin use at one year (OR 0.41, 95% CI 0.35–0.47, p < 0.001) (Table 4). Although pregabalin is only indicated for PNH, there is some evidence supporting its efficacy for acute pain of herpes zoster (21, 22). On the other hand, pregabalin could also be discontinued due to a lack of desired efficacy or the development of intolerable side effects. In fact, adverse effects of pregabalin treatment usually appear early in the treatment course, and usually resolve after prolonged use (11). Premature discontinuation preclude further escalation of the dosage, and thus could also account for the finding that most prescriptions were under-dosed, especially in pain disorders. Both could lead to poor treatment outcomes and hence compromised quality of life. An in-depth understanding of the dynamics of development of adverse events, would be helpful to optimize the prescription of pregabalin.
Among the different indications included, epilepsy patients had the greatest likelihood of long-term use, and PHN the least. Similar findings were reported in the Swedish study mentioned above (16), in which epilepsy and NeP had the best and worst persistence rates during follow-up. Generally speaking, studies evaluating drug treatment in epilepsy usually report high persistence or adherence rates (23–25). This could probably be attributed to the unremitting nature of most seizure disorders, as well as the devastating and potentially life-threating consequences of not receiving treatment. In contrast, in the American study mentioned above, the low persistence rate of pregabalin use in the treatment of NeP was, at least in part, attributed to suboptimal dosing, with 87% reaching ≥ 150 mg/day and 27% reaching ≥ 300 mg/day (15), which were higher than the corresponding figures of 62.5% and 6.4%, respectively, in the present study (Table 3). Besides, the average doses prescribed for NeP (147.2 ± 100.3 mg for PHN, 131.2 ± 93 mg for DPNP) (Table 3) were lower than those in the American (187 mg for PHN) (15) and Swedish studies (275 mg for NeP) (16). The tolerability of pregabalin was reported to be comparable to that of placebo in clinical trials (10, 12–14). However, the majority of pivotal trials were carried out in North America and/or Europe. In fact, side effects, such as dizziness, somnolence, peripheral edema, and weight gain, were more common among Asians as compared to Caucasians (11). This could result from increased exposure to pregabalin due to the relatively lower average body weights among Asian patients, which could result in decreased tolerability, and possibly lower average doses prescribed.
The most important strength of the present study is the large-scale sample recruited, and the almost complete coverage of our NHI leads to the relative freedom from selection bias of the dataset. Besides, the data from NHIRD have been validated by a number of studies, and have yielded important findings that are widely accepted (26–28). On the other hand, the main weaknesses include the validity of the diagnosis coding and the lack of relevant clinical information regarding the initiation and discontinuation of the prescription. PHN or DPNP, and fibromyalgia could not be accurately coded in the ICD-9-CM coding system, and this remains an issue in the ICD-10 coding system, except for fibromyalgia. Besides, it could be possible that fibromyalgia could be miscoded as other musculoskeletal diseases. However, when these diagnosis codes were associated with pregabalin prescriptions concomitantly, the probability that these codes correspond to the designated diagnoses should be high. Despite the above weaknesses, the present study could still provide some useful information regarding the pattern of pregabalin prescriptions in our country.