Web-based intensive monitoring gives an overview of the safety profile of duloxetine in daily practice as well as capturing the characteristics of its users.
In the study the majority (69.1 %) of participants were female, which is consistent with the fact that both depression and neuropathic pain are more prevalent in women [16, 17]. The ages ranged from 14 to 82 years with 2 patients below 18 years of age. Duloxetine is registered for use in adults  and this shows that duloxetine, although it is a relatively new drug, is prescribed to younger patients off label. The majority of patients started with the 30-mg capsule and the average daily dosage was 49.1 mg, which is low compared with the recommended starting dosage of 60 mg once daily for the treatment of depression and diabetic peripheral neuropathic pain . In this study duloxetine is used mostly as a treatment for depression; only 16.1 % of the patients used duloxetine for neuropathic pain. This is quite surprising since there were many treatment options for depression on the market at the time of the introduction of duloxetine, but few drugs registered for the treatment of neuropathic pain. However, many of the patients who received duloxetine stated that they had used other drugs for the same indication in the past, and SSRIs, together with TCAs and other antidepressant drugs were the most frequently mentioned, indicating that the patients who receive duloxetine did not respond to treatment with other antidepressant drugs. Another possibility is that the prevalence of depression is higher than the prevalence of neuropathic pain. It is surprising that almost 5 % stated that they used duloxetine for the treatment of fibromyalgia, even though this is not a registered indication in the European Union; however, in the USA duloxetine is indicated for the treatment of fibromyalgia . Just as the intensive monitoring study of pregabalin, which is another drug indicated for the treatment of neuropathic pain, showed , it seems that duloxetine is prescribed to patients with fibromyalgia off label in the Netherlands.
Adverse drug reactions
The ADRs most frequently reported in this study correspond to the most frequently reported ADRs in pre-registration trials, as well as in other trials [2–6, 19, 20]. The frequencies obtained with the LIM system are similar to those stated in the EPAR, except for a few cases. Of the possible ADRs reported via the web-based intensive monitoring system, three are worth additional attention.
Two reports of amenorrhea were reported. Even though the age of the patients (49 and 45 years old respectively) suggest that the amenorrhea could be due to the women entering the menopause, the absence of other symptoms relating to the menopause as well as the positive dechallenge in one case supports a causal relationship. Amenorrhea is not listed in the EPAR of duloxetine (the unspecified menopausal symptoms are), but can be explained from a mechanistic point of view as it is a clinical manifestation of hyperprolactinaemia that is mentioned in the EPAR and is caused by raised levels of serotonin, which is a modulator of prolactin secretion .
Shock-like paraesthesia consists of sensory perceptions of short electric low-voltage discharges, usually localised in the brain. In addition to these two reports, the Netherlands Pharmacovigilance Centre received three reports of shock-like paraesthesia through their spontaneous reporting system, strengthening this signal . Shock-like paraesthesia has been described with the use of SSRIs [23, 24]. The symptoms usually occur during drug withdrawal, but have also been described with ongoing therapy. As it might not always be recognised as an ADR by patients and health care professionals, it is worth paying extra attention to it.
The EPAR for duloxetine mentions urinary disorders except dysuria as being uncommon (frequency 0.1–1 %). In the LIM cohort urinary disorders were reported more frequently; a total of 17 patients reported urinary disorders, mainly urinary hesitation and increased micturition frequency. It is notable that 11 of the 17 patients (64.7 %) with urinary problems were men, since only 30 % of the cohort are men. Only one of the men reported the use of drugs for treatment of benign prostate hypertrophy, which might be a confounding factor for the urinary disorders. The low frequency in the EPAR is surprising, especially for urinary hesitation, since duloxetine is registered under another brand name (Yentreve®), which is indicated for stress urinary incontinence .
Strengths and weaknesses
Web-based intensive monitoring is an observational prospective cohort study mirroring the use and ADRs of duloxetine in daily practice compared with clinical studies, which have strict inclusion and exclusion criteria.
Eligible patients were identified in community pharmacies; however, not all patients eligible for inclusion participated in the study. Data on duloxetine dispensing during the inclusion period were provided by the Dutch Foundation for Pharmaceutical Statistics  and the LIM response rate was 3.5 % of all patients receiving a first prescription of duloxetine during the inclusion period. This might contribute to non-response bias. There is no information about the patients who did not participate; it is therefore not possible to know if the patients eventually participating in the study are representative of all patients using duloxetine. Non-response bias in a LIM study has been investigated and it showed that patients participating in LIM are in general younger and use a little less co-medication (0.8) than non-responders (Härmark et al., submitted for publication). However it cannot be assumed that younger patients experience fewer ADRs than older patients [27, 28].
In this study it was chosen to use the patient as a source of information. This has the advantage that adverse drug reactions are reported by the person who has actually experienced the reaction. Since patients do not have any “professional filter” in what they report, compared with health professionals, it enhances the chance of finding new ADRs that would not be considered ADRs, and therefore not reported by health professionals. For example, shock-like paraesthesias is an ADR that is primarily reported by patients compared with health professionals at the Netherlands Pharmacovigilance Centre Lareb. Since the patient is the source of information, it might be difficult to obtain information about fatal outcomes. In this study we received one report with a fatal outcome, and this was reported by the patient’s wife, showing that patient-based tools can also collect information about fatal outcomes.
It is surprising that almost 80 % of the patients who filled in a questionnaire reported an ADR. This is a rather high percentage and it is possible that patients who experienced an ADR were more inclined to fill in a questionnaire than those who did not experience ADRs, but analyses showed no difference in gender, age, and daily duloxetine dosage between the groups. Another reason for the high percentage might be channeling. Forty percent of the participants had in the past used one or more drugs for the same indication. It is not known if they switched because of a lack of efficacy or because of ADRs. If the latter were the reason for switching, it can be assumed that these patients might have an increased susceptibility to ADRs compared with others.