Development of a 3D-Printed Dosing Platform to Aid in Zolpidem Withdrawal Therapy

The long-term use of benzodiazepine receptor agonists (BZRAs) is associated with multiple side effects, such as increased sedation, hangover or an elevated risk of dependency and abuse. Unfortunately, the long-term use of BZRAs is reaching worrying intake rates, and therefore, the need for action is high. It was demonstrated already that the overall willingness of patients for deprescription increased when a slow dose reduction scheme with the possibility for dose increase, if needed, is employed. The current study aims to develop a flexible dosing platform of zolpidem hemitartrate (ZHT) to facilitate such withdrawal therapy. As this is the first report on the extrusion and 3D printing of ZHT, its thermal behaviour and sensitivity towards photolytic degradation was characterised. It was shown that ZHT possesses multiple polymorphs and was especially prone to oxidative photolysis. Next, a variety of immediate release polymers (Eudragit EPO, Kollidon VA64, Kollidon 12PF and Soluplus) were blended and extruded with Polyox WSR N10 to investigate their feedability and printability by mechanical and rheological analysis. The addition of PEO was shown to enable printing of these brittle pharmaceutical polymers, although the processing temperature was deemed critical to avoid surface defects on the resulting filaments. An EPO(70)PEO(30) system was selected based on its suitable mechanical properties and low hygroscopicity favoring ZHT stability. The matrix was blended with 1% or 10% API. The effect of certain printing parameters (caplet size, nozzle diameter, % overlap) on dissolution behaviour and caplet weight/dimensions/quality was assessed. A flexible dosing platform capable of delivering <1 mg and up to 10 mg of ZHT was created. Either caplet modification (incorporation of channels) or disintegrant addition (Primojel, Explotab, Ac-Di-Sol, Primellose and Polyplasdone-XL) failed to achieve an immediate release profile. This study provides the first report of a 3D-printed flexible dosing platform containing ZHT to aid in withdrawal therapy.

Meta-analysis of prednisone in withdrawal therapy following medication overuse headache

The objective of this meta-analysis was to evaluate the therapeutic effectiveness of prednisone in withdrawal therapy following medication overuse headache. The Cochrane, PubMed, EMBASE, Web of Science, CNKI, VIP, and Wanfang data were searched to identify randomized control trials of prednisone for the treatment of medication overuse headache. Two researchers independently screened published studies according to inclusion and exclusion criteria, and evaluated the methodological quality of included studies. Revman 5.3 software was used to analyze the extracted data, and a total of six randomized control trials involving 510 patients were included in the study. Meta-analysis indicated that there was no significant difference in the ratio of taking painkillers again after withdrawal (RR=0.89, 95% CI: 0.70,1.14, P=0.36) compared with the control group. There was also no significant difference between the experimental group and the control group in the incidence of withdrawal reactions (RR=1.28, 95% CI: 0.87, 1.89, P=0.21), severity of headache (RR=1.56, 95% CI: -4.83, 7.95, P=0. 63) and the frequency of headache attacks after withdrawal (RR=0.14, 95% CI: -0.35, 0.63, P=0.58). It is concluded that prednisone does not alleviate symptoms in patients with medication overuse headache after withdrawal.

Medication Overuse Headache

Medication overuse headache (MOH) is defined in the latest ICHD-3 criteria as a secondary headache caused by worsening of a pre-existing headache (usually a primary headache) owing to overuse of one or more attack-aborting or pain-relieving medications. MOH can be debilitating and results from biochemical and functional brain changes induced by certain medications taken too frequently. Various risk factors some modifiable, other non-modifiable (Multiple Gene Polymorphisms) have been hypothesised in MOH. Psychiatric co-morbidities in MOH are noticeably (anxiety and depression) found to be co morbid disorders by more than chance. This has to be managed effectively along with treatment strategies for MOH for efficacious response to withdrawal treatment. Ample literature and clinical evidence shown in prospective trials, that withdrawal therapy is the best treatment for MOH. The mainstay of MOH treatment is not only to detoxify the patients and to stop the chronic headache but also, most likely, to improve responsiveness to acute or prophylactic drugs. Studies advocating prophylactic treatment with good response to mainly topiramate and OnabotulinumtoxinA do exist, less prominent for prednisolone, however, not recommended for every patient. Management may be complex and must be done via MDT approach with involvement of specialists when needed along with incorporating adequate treatment of acute withdrawal symptoms, educational and behavioural programs to ensure patient understanding of the condition and compliance. There are arguments on either sides of inpatient and outpatient withdrawal for MOH patients dependent heavily on the individual circumstances i.e. patient’s motivation, the duration of the overuse, the type of overused drugs, possible previous history of detoxification failures and co morbidities. Treatment trials are still required to determine for clinicians the best evidence-based approach for helping these patients break their headache cycle.

Medication overuse headache in 787 patients admitted for inpatient treatment over a period of 32 years

Background Definitions of medication overuse headache have changed over time. Objective To evaluate the clinical characteristics of medication overuse headache patients admitted for inpatient withdrawal therapy over a period of 32 years. Methods We included all patients with medication overuse headache treated from 1 January 1984 to 31 December 2015. We obtained all data from the medical reports and defined three periods, P1 (1984–1993), P2 (1994–2003), and P3 (2004–2015). The p-value adjusted for multiple comparisons was set to 0.005. Results Within 32 years, a total of 787 patients accounted for 904 admissions for MOH. From P1 to P3, the proportion of patients with preexisting migraine increased from 44.3% to 53.3% (chi2 = 9.0, p = 0.01) and that with preexisting tension-type headache decreased from 47.9% to 34.6% (chi2 = 9.3, p < 0.01). The median time since onset of headache and medication overuse headache decreased from 20 to 15 years ( p < 0.001) and from 3 to 2 years ( p < 0.001). The median cumulative number of single doses decreased from 120 to 90 per month ( p = 0.002). Overuse of triptans, non-opioid analgesics, and opioids increased, whereas overuse of ergotamines decreased over time ( p < 0.001 for all tests). The use of prophylactic medication before admission increased from 8.3% to 29.9% (chi2 = 89.5, p < 0.001). Conclusion This retrospective study in a large number of patients with medication overuse headache admitted for inpatient withdrawal therapy over a period of 32 years shows a trend towards changes in the preexisting headache type, a decrease in the time since onset of headache and medication overuse headache, a decrease in the number of drug doses used per month, changes in the type of drugs overused, and an increase in, but still low rate, of prophylactic medication prior to admission.

Validity of self-reported assessment of Severity of Dependence Scale in Medication-Overuse Headache

The interview-based Severity of Dependence Scale (SDS) predicts the outcome of withdrawal therapy in Medication-Overuse Headache (MOH). We aimed to compare the interview-based SDS with a self-administrated written version. Fifty-three MOH patients, 19 chronic headache patients without medication overuse and 25 population controls were recruited from a previous randomized controlled trial. The SDS was scored in a telephone interview by headache experts, further, the participants filled in the SDS as a part of a self-administered questionnaire. The SDS assesses scores dependence through five questions, each scored from 0 to 3. A score of ≥5 is associated with MOH. Mean SDS scores were 2.8 (SD 3.0) vs. 3.1 (SD 2.9), p = 0.12, for the interview vs. the self-reported questionnaire, with a correlation 0.78. There was a non-significant bias of 0.32 (95% limits of agreement of −3.6; 4.2) between the two methods in the Bland-Altman analysis. A self-reported SDS questionnaire can be used, and may yield valuable information as a screening tool prior to headache consultations or studies. The possibilities of designing web-based self-treatment tools based on SDS self-assessment and brief intervention may be a future approach for a large group of patients.

Oxygen delivered by a high flow concentrator for the treatment of medication-overuse headache

Treatment of medication-overuse headache (MOH) relies on detoxification, during which patients face rebound headache without alternative to painkiller. As oxygen has been proven effective for cluster and other headache subtypes, we sought to evaluate use of normobaric oxygen delivered by a high flow concentrator (HFC) in patients suffering MOH. For this purpose, twenty patients with MOH were included in this prospective monocentric open-labeled feasibility study. All patients received standard care with detoxification in addition to HFC delivering normobaric oxygen at 9 l/min, used to their discretion to treat rebound headache. Primary endpoint was acceptance of HFC and secondary endpoints evaluated its efficacy. Four patients were lost of follow-up after inclusion, one was excluded. HFC was accepted by 14/15 (93.3%). At M6 of follow-up, 15/15 (100%) reverted to episodic headache. In conclusion, normobaric oxygen delivered by HFC appears to be safe, feasible, and probably efficient to help patient with MOH who undergo withdrawal therapy. A larger double-blind, sham-controlled prospective study is needed. Trial registration: Clinical trials: NCT02302027.

Chronic headache with medication overuse: Long-term prognosis after withdrawal therapy

Background Knowledge about long-term outcomes after medication withdrawal therapy for chronic headache, including tension type and migraine headache is lacking. Methods We re-examined 56 patients an average of nine years after they participated in a medication withdrawal study with a one-year follow-up. We collected and compared data on headache, use of medication, quality of life, quality of sleep, anxiety, depression, and labor participation one and nine years after the start of withdrawal therapy. Results Headache days per month decreased from 16.7 (14.0–19.3) at one year to 13.3 (10.6–15.9) at nine years (P = 0.007). The proportion of patients meeting the criteria for chronic headache decreased from 27/56 (48%) at one year to 18/56 (32%) at nine years (P = 0.004). Medication overuse was reported in seven (13%) patients at one year and 18 (32%) at nine years (P = 0.013). The majority of patients overusing medication at nine years (10/18) belonged to a group of 14 patients who had a poor early response to withdrawal therapy and had sustained chronic headache after nine years. After excluding patients receiving retirement pensions, the proportion who received disability benefits increased from 21/55 (38%) at one year to 30/49 (61%) at nine years (P = 0.003). Conclusion Improvements after withdrawal therapy for chronic headache last at least nine years, with a parallel increase in the use of disability benefits. However, a high proportion of patients with a poor initial response to withdrawal therapy and sustained chronic headache overuse medication.