Фармакологично повлияване на болката: експериментални, клинични и регулаторни проучвания
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Дата
2018-09-07
Автори
Тодорова/Todorova, Любина Рачева/Lyubina Racheva
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ISSN на списанието
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Издател
Резюме
***** ЦЕЛ И ЗАДАЧИ ***
Цел:
Експериментални, клинични и регулаторни проучвания относно оптимизиране на отношението ефективност/риск на антиконвулсанти при различен тип невропатна болка; Оценка на актуалното състояние на разрешените за употреба в страната лекарствени продукти за овладяване на невропатна болка и до каква степен те отговарят на препоръките за приложение при пациенти в старческа възраст. *****
Задачи:
1. Разработване на експериментални модели на невропатна болка и повлияването ѝ от габапентиноиди
2. Проследяване ефективността на gabapentin и pregabalin върху промените в болковия праг при два експериментални модела [хронична констриктивна увреда на периферен нерв (CCI) и стрептозотоцин-индуциран модел на захарен диабет (STZ-модел на експериментално предизвикан захарен диабет)] с три теста за болка: Paw withdrawal test, Рlantar heat test и Incapacitance test, отразяващи специфични механизми на алодиния и термална хипералгезия.
3. Клинично проследяване ефективността и нежеланите лекарствени реакции при употребата на gabapentin и pregabalin при пациенти със захарен диабет и болезнена диабетна полиневропатия. Установяване ролята на антиконвулсантите в рационалната фармакотерапия на невропатната болка при пациенти със сходни демографски (пол и възраст) и клинични характеристики (наличие на корелация с типа диабет – тип 1 и тип 2).
4. Установяване до каква степен при разработването от компаниите и оценката от страна на регулаторните органи на съотношението полза риск на лекарствените продукти се вземат предвид специфичните аспекти за безопасност и ефикасност, свързани със старческата възраст.
5. Преглед на одобрените терапевтични индикации за лекарствените продукти, препоръчвани от различните международни указания/ръководства за лечение на невропатна болка и установяване на това дали е хармонизирана информацията (КХП) на различните продукти с тази на референтния продукт?
6. Включена ли е информация за дозировка и начин на приложение/специални предупреждения и предпазни мерки при употреба за популацията от пациенти над 65 години и дали информацията, предоставяна на медицинските специалисти и пациентите е в съответствие с подкрепящата разрешението за употреба клинична документация?
7. Идентифициране на потенциалните регулаторни пропуски и предлагане на мерки за преодоляването им. ***** SUMMARY
After years of neglect, the medical problems related to pain as a medical problem and its treatment attract attention of healthcare profesionals and public. The main reasons for that include high prevalence of pain, persistent evidence of undertreatment, and an increasing number of reports of unintended consequences of inadequate treatment methods.
Persistent pain in elderly patients is a widespread problem associated with the relatively high level of disease in this patient population. There are lots of local regulatory issues and inconsistencies related to the meidcinal products used to relieve complaints of neuropathic pain in special patient populations, particularly in the elderly (over 65 years of age).
According to EUROSTAT forecasts, over 21% of Bulgarian population will be over 65 years of age in 2020 (17.2% in 2005, 17.8% in 2010, and 2030 expected to reach 25.6%). The large heterogeneity of the health status in the elderly affects the effect of neuropathic pain, the assessment of pain and co-morbities and the choice of therapy, especially in people with impaired general condition. In view of this, and given the specific pharmacokinetic changes in this patient population, we believe that the need to define specific requirements for overall information on medicinal products as regards their use in the elderly is ripe.
In the present dissertation are presented experimental and clinical observations, results of the treatment of neuropathic pain with modern methods and adverse drug reactions as well as regulatory problems with the medicinal products recommended for the treatment of neuropathic pain and their use in elderly patients.
Objective: Experimental, clinical and regulatory studies on optimizing the efficacy / risk ratio of anticonvulsants in different types of neuropathic pain
Materials and methods used: Male white rats (Wistar), weighing 200-220 g. Eight (8) experimental animals were included in each of the groups. Sigma-Aldrich substances were used as well as Neurontin (gabapentin) and Lyrica (pregabalin). All in vivo experiments and manipulations have been approved by the Ethics Committee for Research at the Medical University of Sofia.
Valid models of neuropathic pain and diabetes mellitus were used as follows: CCI and STZ-induced diabetes mellitus. The development of neuropathy was traced over time by paw withdrawal test and plantar heat test. The disorders in the hind paws were assessed by an incapacitance test. To verify the progression of hyperalgesia or allodynia, pain hypersensitivity has been evaluated several times before CCI (baseline), on day 14 post surgery and on day 21 of STZ-induced diabetes. Using a stomach tube, orally, gabapentin (60 mg / kg) [the trade name Neurontin, MAH Pfiser Europe MA EEIG, UK] or pregabalin (30 mg / kg) [the trade name Lyrica, PRS Pfizer Limited, UK ] dissolved in 2 ml of saline have been administered.
After the CCI, at day 14 it was found that rats with a CCI model of neuropathic pain showed typical behavioral symptoms of spontaneous pain (limb support, avoiding the injured limb). Studies performed on day 14 show marked tactile and thermal hyperalgesia. One hour after the administration of gabapentin and pregabalin, a re-evaluation of the various manifestations of neuropathic pain was performed.
One hour after the oral administration of gabapentin (60 mg / kg) or pregabalin (30 mg / kg), the paw withdrawal threshold (PWT) was significantly increased in response to tactile (von Frey) stimuli. Simultaneously, a plantar heat test was performed. Paw withdrawal time is similar in both groups of animals. The results show that drugs significantly weaken the thermal hyperalgesia in the plantar heat test (P <0.05) one hour after administration. Latency withdrawal time was similar in the gabapentin (60 mg / kg) or pregabalin (30 mg / kg) groups.
In rats with diabetes, the presence of neuropathy (significant thermal hypersensitivity) was assessed on day 21 after the onset of diabetes. The administration of gabapentin (60 mg / kg) significantly increased the paw withdrawal threshold in PWT. The lower paw withdrawal threshold in rats with diabetes recovered to normal after pregabalin administration. Latency withdrawal time was similar in the gabapentin (60 mg / kg) or pregabalin (30 mg / kg) groups. Graphical differences are not statistically significant.No significant weight loss was seen in rats with diabetes, and none of the two active substances tested altered the baseline.
The clinical trial was conducted in 130 patients with type 1 and type 2 diabetes mellitus, with diagnosed painful diabetic polyneuropathy with duration of complaints more than 12 months and pain intensity over 40 mm as assessed by VAS. Patients were treated with gabapentin or pregabalin at the recommended doses. Four visits were conducted, during each of them the intensity of the pain (VAS) was assessed. The patient groups were comparable in terms of gender, age, and baseline clinical characteristics.
In order to determine whether the intensity of pain significantly decreased during the course of treatment, a dispersion analysis was performed for each patient group, as well as a post-hoc analysis of disperse pairs was also performed.
A positive and reliable correlation between pain intensity after 6 months of treatment with gabapentin and pregabaline and baseline VAS was found. Such a correlation with the age of the patients is lacking. The ratio of men: women in groups with missing and mild pain is the same. The mean age and pain value of VAS (mm) as baseline did not differ significantly. However, the results may also be due to the fact that the sample is small or that the distribution of the values is not in the whole spectrum.
Groups of patients with type 1 and type 2 diabetes mellitus treated with gabapentin and pregabalin did not differ reliably from the mean values for pain intensity at baseline. The percentage of patients treated with pregabalin after 6 months, with no pain was 1.6 times greater than that of patients treated with gabapentin (50% vs. 31%). At the sixth month of the study, at the last visit, the proportion of patients treated with gabapentin with "mild pain" was 1.4 times higher than that of pregabalin patients. In the treatment process, mean VAS (mm) in the "mild pain" group decreased, but with gabapentin they were higher than with pregabalin.
The Mann-Whitney test showed significant differences between groups of patients with type 1 diabethes who had been treated for 6 months with gabapentin and pregabalin at the mean pain reduction rate. The same is true for patients with type 2 diabetes. No correlation has been established between the efficacy of the two active substances in reducing the pain and age of the patients. Gabapentinoids were found to be well tolerated and no treatment was required due to unexpected and / or serious ADRs.
Regarding the regulatory issues, to be identified a systematic literature review of the documentation available in the BDA on medicinal products included in the recommendations for the treatment of neuropathic pain has been conducted. Selected medicinal products for analysis have been identified as being recommended for the treatment of neuropathic pain and relevant to the elderly population, including both medicinal products authorized for use via national procedure and those authorized for use under DCP/MRP. The materials used are related to the documentation of national authorization procedures of medicinal products, which is regulated by the LMPHM. The analysis was made to assess whether data on the geriatric population were accurately presented in product information.
The dossier of 11 active substances, which are comprised of 70 medicinal products authorized in Bulgaria and / or other Member States, have been reviewed.. 11 of them did not have a valid marketing authorization in Bulgaria, and for two products the marketing authorization procedure has not yet been completed. 27 products have been authorized under the national procedure and two products are authorized under a centralized procedure.
The safety profiles of generic medicinal products authorized under the LMPMM via NP or DCP / MRP are fully harmonized with those of the reference medicinal products and no omissions or inaccuracies have been identified in their presentation. ADRs are structured according to System-Organ-Class and frequency requirements and are in compliance with the supporting documentation submitted in Modules 2.5 or Module 5 of the dossier for medicinal products.
In the review of the Summary of Product Characteristics of Medicinal Products and supporting documentation, 2 large groups of medicinal products were identified as follow: Products licensed after 2007, taking into account current regulatory standards, especially those authorized for use under DCP / MRP fully comply with the standards and the reference product for the active substance. For medicinal products authorized decades ago, via pure national procedure, significant information gaps for elderly patients (> 65 years) have been identified.
In 48% of the medicinal products authorized prior to 2007 (purely national procedure):
• Inconsistencies with the reference product;
• Discrepancies with safety information between generic products;
• Missing safety information;
To sum up:
1. Gabapentin and pregabalin reduce tactile and thermal hypersensitivity in rats. The effect is comparable in rat with CCI or STZ-induced diabetic neuropathy.
2. Non-clinical and clinical studies with gabapentin and pregabalin demonstrated that these drugs are effective agents for relieving neuropathic pain with a very good safety profile.
3. Gabapentin and pregabalin are effective aduvant analgesics for patients with diabetic neuropathy. Pregabalin demonstrates higher efficacy than gabapentin in long-term use.
4. At the end of the sixth month, we found a significant difference in the effects of pregabalin and gabapentin (P <0.05). There was no correlation between the efficacy of the two active substances in reducing the pain, gender and age of the patients as well as in the type of diabetes mellitus.
5. All products authorized for use under the Medicines and Pharmacies in Human Medicine Act (1995) and supporting documentation of the MA at the time of the study do not meet the current regulatory requirements.
Описание
Дисертационен труд за придобиване на образователна и научна степен „доктор“
Направление 7: Здравеопазване и спорт ; Професионално направление: 7.1.Медицина
Научна специалност: Фармакология ; (вкл. Фармакокинетика и химиотерапия)
Научни Ръководители:
Проф. д-р Славина Сурчева, дм
Проф. д-р Димитър Масларов, дм
Научен консултант:
Чл. Кор. Проф. Д-р Мила Власковска, дм, дмн
Рецензенти
Доц. д-р Иван Тодоров Ламбев, дм
Доц. д-р Румен Павлов Николов, дм
София 2018
Ключови думи
Хронична болка; фармакологично третиране; габапентиноиди - странични ефекти; експериментално проследяване; клинични проучвания; регулаторни въпроси , chronic pain; pharmacologic treatment; gabapentinoids - adverse effects; experiments; clinical examinations; regulatory problems