Journal of Clinical and Diagnostic Research, ISSN - 0973 - 709X

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Dr Bhanu K Bhakhri

"The Journal of Clinical and Diagnostic Research (JCDR) has been in operation since almost a decade. It has contributed a huge number of peer reviewed articles, across a spectrum of medical disciplines, to the medical literature.
Its wide based indexing and open access publications attracts many authors as well as readers
For authors, the manuscripts can be uploaded online through an easily navigable portal, on other hand, reviewers appreciate the systematic handling of all manuscripts. The way JCDR has emerged as an effective medium for publishing wide array of observations in Indian context, I wish the editorial team success in their endeavour"



Dr Bhanu K Bhakhri
Faculty, Pediatric Medicine
Super Speciality Paediatric Hospital and Post Graduate Teaching Institute, Noida
On Sep 2018




Dr Mohan Z Mani

"Thank you very much for having published my article in record time.I would like to compliment you and your entire staff for your promptness, courtesy, and willingness to be customer friendly, which is quite unusual.I was given your reference by a colleague in pathology,and was able to directly phone your editorial office for clarifications.I would particularly like to thank the publication managers and the Assistant Editor who were following up my article. I would also like to thank you for adjusting the money I paid initially into payment for my modified article,and refunding the balance.
I wish all success to your journal and look forward to sending you any suitable similar article in future"



Dr Mohan Z Mani,
Professor & Head,
Department of Dematolgy,
Believers Church Medical College,
Thiruvalla, Kerala
On Sep 2018




Prof. Somashekhar Nimbalkar

"Over the last few years, we have published our research regularly in Journal of Clinical and Diagnostic Research. Having published in more than 20 high impact journals over the last five years including several high impact ones and reviewing articles for even more journals across my fields of interest, we value our published work in JCDR for their high standards in publishing scientific articles. The ease of submission, the rapid reviews in under a month, the high quality of their reviewers and keen attention to the final process of proofs and publication, ensure that there are no mistakes in the final article. We have been asked clarifications on several occasions and have been happy to provide them and it exemplifies the commitment to quality of the team at JCDR."



Prof. Somashekhar Nimbalkar
Head, Department of Pediatrics, Pramukhswami Medical College, Karamsad
Chairman, Research Group, Charutar Arogya Mandal, Karamsad
National Joint Coordinator - Advanced IAP NNF NRP Program
Ex-Member, Governing Body, National Neonatology Forum, New Delhi
Ex-President - National Neonatology Forum Gujarat State Chapter
Department of Pediatrics, Pramukhswami Medical College, Karamsad, Anand, Gujarat.
On Sep 2018




Dr. Kalyani R

"Journal of Clinical and Diagnostic Research is at present a well-known Indian originated scientific journal which started with a humble beginning. I have been associated with this journal since many years. I appreciate the Editor, Dr. Hemant Jain, for his constant effort in bringing up this journal to the present status right from the scratch. The journal is multidisciplinary. It encourages in publishing the scientific articles from postgraduates and also the beginners who start their career. At the same time the journal also caters for the high quality articles from specialty and super-specialty researchers. Hence it provides a platform for the scientist and researchers to publish. The other aspect of it is, the readers get the information regarding the most recent developments in science which can be used for teaching, research, treating patients and to some extent take preventive measures against certain diseases. The journal is contributing immensely to the society at national and international level."



Dr Kalyani R
Professor and Head
Department of Pathology
Sri Devaraj Urs Medical College
Sri Devaraj Urs Academy of Higher Education and Research , Kolar, Karnataka
On Sep 2018




Dr. Saumya Navit

"As a peer-reviewed journal, the Journal of Clinical and Diagnostic Research provides an opportunity to researchers, scientists and budding professionals to explore the developments in the field of medicine and dentistry and their varied specialities, thus extending our view on biological diversities of living species in relation to medicine.
‘Knowledge is treasure of a wise man.’ The free access of this journal provides an immense scope of learning for the both the old and the young in field of medicine and dentistry as well. The multidisciplinary nature of the journal makes it a better platform to absorb all that is being researched and developed. The publication process is systematic and professional. Online submission, publication and peer reviewing makes it a user-friendly journal.
As an experienced dentist and an academician, I proudly recommend this journal to the dental fraternity as a good quality open access platform for rapid communication of their cutting-edge research progress and discovery.
I wish JCDR a great success and I hope that journal will soar higher with the passing time."



Dr Saumya Navit
Professor and Head
Department of Pediatric Dentistry
Saraswati Dental College
Lucknow
On Sep 2018




Dr. Arunava Biswas

"My sincere attachment with JCDR as an author as well as reviewer is a learning experience . Their systematic approach in publication of article in various categories is really praiseworthy.
Their prompt and timely response to review's query and the manner in which they have set the reviewing process helps in extracting the best possible scientific writings for publication.
It's a honour and pride to be a part of the JCDR team. My very best wishes to JCDR and hope it will sparkle up above the sky as a high indexed journal in near future."



Dr. Arunava Biswas
MD, DM (Clinical Pharmacology)
Assistant Professor
Department of Pharmacology
Calcutta National Medical College & Hospital , Kolkata




Dr. C.S. Ramesh Babu
" Journal of Clinical and Diagnostic Research (JCDR) is a multi-specialty medical and dental journal publishing high quality research articles in almost all branches of medicine. The quality of printing of figures and tables is excellent and comparable to any International journal. An added advantage is nominal publication charges and monthly issue of the journal and more chances of an article being accepted for publication. Moreover being a multi-specialty journal an article concerning a particular specialty has a wider reach of readers of other related specialties also. As an author and reviewer for several years I find this Journal most suitable and highly recommend this Journal."
Best regards,
C.S. Ramesh Babu,
Associate Professor of Anatomy,
Muzaffarnagar Medical College,
Muzaffarnagar.
On Aug 2018




Dr. Arundhathi. S
"Journal of Clinical and Diagnostic Research (JCDR) is a reputed peer reviewed journal and is constantly involved in publishing high quality research articles related to medicine. Its been a great pleasure to be associated with this esteemed journal as a reviewer and as an author for a couple of years. The editorial board consists of many dedicated and reputed experts as its members and they are doing an appreciable work in guiding budding researchers. JCDR is doing a commendable job in scientific research by promoting excellent quality research & review articles and case reports & series. The reviewers provide appropriate suggestions that improve the quality of articles. I strongly recommend my fraternity to encourage JCDR by contributing their valuable research work in this widely accepted, user friendly journal. I hope my collaboration with JCDR will continue for a long time".



Dr. Arundhathi. S
MBBS, MD (Pathology),
Sanjay Gandhi institute of trauma and orthopedics,
Bengaluru.
On Aug 2018




Dr. Mamta Gupta,
"It gives me great pleasure to be associated with JCDR, since last 2-3 years. Since then I have authored, co-authored and reviewed about 25 articles in JCDR. I thank JCDR for giving me an opportunity to improve my own skills as an author and a reviewer.
It 's a multispecialty journal, publishing high quality articles. It gives a platform to the authors to publish their research work which can be available for everyone across the globe to read. The best thing about JCDR is that the full articles of all medical specialties are available as pdf/html for reading free of cost or without institutional subscription, which is not there for other journals. For those who have problem in writing manuscript or do statistical work, JCDR comes for their rescue.
The journal has a monthly publication and the articles are published quite fast. In time compared to other journals. The on-line first publication is also a great advantage and facility to review one's own articles before going to print. The response to any query and permission if required, is quite fast; this is quite commendable. I have a very good experience about seeking quick permission for quoting a photograph (Fig.) from a JCDR article for my chapter authored in an E book. I never thought it would be so easy. No hassles.
Reviewing articles is no less a pain staking process and requires in depth perception, knowledge about the topic for review. It requires time and concentration, yet I enjoy doing it. The JCDR website especially for the reviewers is quite user friendly. My suggestions for improving the journal is, more strict review process, so that only high quality articles are published. I find a a good number of articles in Obst. Gynae, hence, a new journal for this specialty titled JCDR-OG can be started. May be a bimonthly or quarterly publication to begin with. Only selected articles should find a place in it.
An yearly reward for the best article authored can also incentivize the authors. Though the process of finding the best article will be not be very easy. I do not know how reviewing process can be improved. If an article is being reviewed by two reviewers, then opinion of one can be communicated to the other or the final opinion of the editor can be communicated to the reviewer if requested for. This will help one’s reviewing skills.
My best wishes to Dr. Hemant Jain and all the editorial staff of JCDR for their untiring efforts to bring out this journal. I strongly recommend medical fraternity to publish their valuable research work in this esteemed journal, JCDR".



Dr. Mamta Gupta
Consultant
(Ex HOD Obs &Gynae, Hindu Rao Hospital and associated NDMC Medical College, Delhi)
Aug 2018




Dr. Rajendra Kumar Ghritlaharey

"I wish to thank Dr. Hemant Jain, Editor-in-Chief Journal of Clinical and Diagnostic Research (JCDR), for asking me to write up few words.
Writing is the representation of language in a textual medium i e; into the words and sentences on paper. Quality medical manuscript writing in particular, demands not only a high-quality research, but also requires accurate and concise communication of findings and conclusions, with adherence to particular journal guidelines. In medical field whether working in teaching, private, or in corporate institution, everyone wants to excel in his / her own field and get recognised by making manuscripts publication.


Authors are the souls of any journal, and deserve much respect. To publish a journal manuscripts are needed from authors. Authors have a great responsibility for producing facts of their work in terms of number and results truthfully and an individual honesty is expected from authors in this regards. Both ways its true "No authors-No manuscripts-No journals" and "No journals–No manuscripts–No authors". Reviewing a manuscript is also a very responsible and important task of any peer-reviewed journal and to be taken seriously. It needs knowledge on the subject, sincerity, honesty and determination. Although the process of reviewing a manuscript is a time consuming task butit is expected to give one's best remarks within the time frame of the journal.
Salient features of the JCDR: It is a biomedical, multidisciplinary (including all medical and dental specialities), e-journal, with wide scope and extensive author support. At the same time, a free text of manuscript is available in HTML and PDF format. There is fast growing authorship and readership with JCDR as this can be judged by the number of articles published in it i e; in Feb 2007 of its first issue, it contained 5 articles only, and now in its recent volume published in April 2011, it contained 67 manuscripts. This e-journal is fulfilling the commitments and objectives sincerely, (as stated by Editor-in-chief in his preface to first edition) i e; to encourage physicians through the internet, especially from the developing countries who witness a spectrum of disease and acquire a wealth of knowledge to publish their experiences to benefit the medical community in patients care. I also feel that many of us have work of substance, newer ideas, adequate clinical materials but poor in medical writing and hesitation to submit the work and need help. JCDR provides authors help in this regards.
Timely publication of journal: Publication of manuscripts and bringing out the issue in time is one of the positive aspects of JCDR and is possible with strong support team in terms of peer reviewers, proof reading, language check, computer operators, etc. This is one of the great reasons for authors to submit their work with JCDR. Another best part of JCDR is "Online first Publications" facilities available for the authors. This facility not only provides the prompt publications of the manuscripts but at the same time also early availability of the manuscripts for the readers.
Indexation and online availability: Indexation transforms the journal in some sense from its local ownership to the worldwide professional community and to the public.JCDR is indexed with Embase & EMbiology, Google Scholar, Index Copernicus, Chemical Abstracts Service, Journal seek Database, Indian Science Abstracts, to name few of them. Manuscriptspublished in JCDR are available on major search engines ie; google, yahoo, msn.
In the era of fast growing newer technologies, and in computer and internet friendly environment the manuscripts preparation, submission, review, revision, etc and all can be done and checked with a click from all corer of the world, at any time. Of course there is always a scope for improvement in every field and none is perfect. To progress, one needs to identify the areas of one's weakness and to strengthen them.
It is well said that "happy beginning is half done" and it fits perfectly with JCDR. It has grown considerably and I feel it has already grown up from its infancy to adolescence, achieving the status of standard online e-journal form Indian continent since its inception in Feb 2007. This had been made possible due to the efforts and the hard work put in it. The way the JCDR is improving with every new volume, with good quality original manuscripts, makes it a quality journal for readers. I must thank and congratulate Dr Hemant Jain, Editor-in-Chief JCDR and his team for their sincere efforts, dedication, and determination for making JCDR a fast growing journal.
Every one of us: authors, reviewers, editors, and publisher are responsible for enhancing the stature of the journal. I wish for a great success for JCDR."



Thanking you
With sincere regards
Dr. Rajendra Kumar Ghritlaharey, M.S., M. Ch., FAIS
Associate Professor,
Department of Paediatric Surgery, Gandhi Medical College & Associated
Kamla Nehru & Hamidia Hospitals Bhopal, Madhya Pradesh 462 001 (India)
E-mail: drrajendrak1@rediffmail.com
On May 11,2011




Dr. Shankar P.R.

"On looking back through my Gmail archives after being requested by the journal to write a short editorial about my experiences of publishing with the Journal of Clinical and Diagnostic Research (JCDR), I came across an e-mail from Dr. Hemant Jain, Editor, in March 2007, which introduced the new electronic journal. The main features of the journal which were outlined in the e-mail were extensive author support, cash rewards, the peer review process, and other salient features of the journal.
Over a span of over four years, we (I and my colleagues) have published around 25 articles in the journal. In this editorial, I plan to briefly discuss my experiences of publishing with JCDR and the strengths of the journal and to finally address the areas for improvement.
My experiences of publishing with JCDR: Overall, my experiences of publishing withJCDR have been positive. The best point about the journal is that it responds to queries from the author. This may seem to be simple and not too much to ask for, but unfortunately, many journals in the subcontinent and from many developing countries do not respond or they respond with a long delay to the queries from the authors 1. The reasons could be many, including lack of optimal secretarial and other support. Another problem with many journals is the slowness of the review process. Editorial processing and peer review can take anywhere between a year to two years with some journals. Also, some journals do not keep the contributors informed about the progress of the review process. Due to the long review process, the articles can lose their relevance and topicality. A major benefit with JCDR is the timeliness and promptness of its response. In Dr Jain's e-mail which was sent to me in 2007, before the introduction of the Pre-publishing system, he had stated that he had received my submission and that he would get back to me within seven days and he did!
Most of the manuscripts are published within 3 to 4 months of their submission if they are found to be suitable after the review process. JCDR is published bimonthly and the accepted articles were usually published in the next issue. Recently, due to the increased volume of the submissions, the review process has become slower and it ?? Section can take from 4 to 6 months for the articles to be reviewed. The journal has an extensive author support system and it has recently introduced a paid expedited review process. The journal also mentions the average time for processing the manuscript under different submission systems - regular submission and expedited review.
Strengths of the journal: The journal has an online first facility in which the accepted manuscripts may be published on the website before being included in a regular issue of the journal. This cuts down the time between their acceptance and the publication. The journal is indexed in many databases, though not in PubMed. The editorial board should now take steps to index the journal in PubMed. The journal has a system of notifying readers through e-mail when a new issue is released. Also, the articles are available in both the HTML and the PDF formats. I especially like the new and colorful page format of the journal. Also, the access statistics of the articles are available. The prepublication and the manuscript tracking system are also helpful for the authors.
Areas for improvement: In certain cases, I felt that the peer review process of the manuscripts was not up to international standards and that it should be strengthened. Also, the number of manuscripts in an issue is high and it may be difficult for readers to go through all of them. The journal can consider tightening of the peer review process and increasing the quality standards for the acceptance of the manuscripts. I faced occasional problems with the online manuscript submission (Pre-publishing) system, which have to be addressed.
Overall, the publishing process with JCDR has been smooth, quick and relatively hassle free and I can recommend other authors to consider the journal as an outlet for their work."



Dr. P. Ravi Shankar
KIST Medical College, P.O. Box 14142, Kathmandu, Nepal.
E-mail: ravi.dr.shankar@gmail.com
On April 2011

Important Notice

Original article / research
Year : 2012 | Month : May | Volume : 6 | Issue : 4 | Page : 682 - 687

A Synergistic Approach to evaluate the Anti-Nociceptive Activity of a GABA Agonist with Opioids in Albino Mice

G. Francis Britto, K.R. Subash, N. Jagan Rao, Binoy Varghese Cheriyan, S. Vijay Kumar

1. Corresponding Author 2. Department of Pharmacology, IRT-PMC, Sanatorium (post), Perundurai, Erode, TN 3. Department of Pharmacology, Meenakshi Medical College and RI, Kanchipuram, TN 4. Department of Pharmacology, Meenakshi Medical College and RI, Kanchipuram, TN 5. Department of Pharmacology, Meenakshi Medical College and RI, Kanchipuram, TN, India.

Correspondence Address :
Dr. G. Francis Britto,
Department of pharmacology, IRT-PMC, Sanatorium (post),
Perundurai, Erode, TN.
PIN: 638053
Phone:09025154465
E-mail: stbritto@hotmail.com

Abstract

Opioids constitute the first-line treatment for pain and they provide a potent analgesic effect, but they are also responsible for various adverse effects such as nausea, vomiting, sedation, constipation and respiratory depression, which seriously limit their use. The purpose of this study was to evaluate whether a GABA agonist which was given along with opioids at a minimal dose could elicit an anti-nociceptive activity in albino mice or not, as compared to morphine. Analgesia evaluation by using the acute pain model hotplate method was employed. The GABA agonists Gabapentin, Baclofen, Tiagabine and Vigabatrine with opioids Morphine and Tramadol, separately, at minimal doses, were given to mice and they were compared with a morphine analgesic dose. Morphine 3mg/kg showed a significant analgesic effect. This dose hot plate latency was taken as a standard and this was compared with all the test drugs which were used in this study. Morphine 1mg/kg (low dose) alone showed minimal antinociception, whereas in combination with a low dose GABA agonist, it showed significant antinociception. Tramadol 20mg/kg showed a significant analgesic effect and Tramadol 10mg/kg (low dose) showed a minimal analgesic effect, whereas the low dose Tramadol with the low dose GABA agonists in a combination showed a significant analgesic effect as that of Morphine 3mg/kg. The combination of a minimal dose of opioid and a GABA agonist has a significant anti nociceptive activity

Keywords

GABA, Opioids, Anti-nociceptive, Hot Plate

Introduction
Pharmacological treatments are undeniably the most common approach to treat pain. Earlier, mankind was dependent on herbs like Cichorium intybus and Solanum nigrum for hepatoprotection (1) and they were mostly dependent on opium for pain. Today, several pharmacological classes of drugs include a natural product prototype. Aspirin, atropine, ephedrine, digoxin, morphine, quinine, reserpine and tubocurarine are a few examples of the modern drugs which were originally discovered through the study of traditional cures and the folk knowledge of indigenous people (2). Several peptide drugs are in the stages of preclinical and clinical development for the treatment of severe pain which is often associated with diseases such as cancer (3). In the clinical practice, the recent advances have been based upon improved understanding of ‘old’ substances such as Morphine and at the same time, the research continues in the hope of finding the ‘ideal’ analgesic which is effective in most of the situations but without adverse effects (4). The methods of treatment are different for acute and chronic pain. For acute pain, analgesics such as nonsteroidal anti-inflammatory drugs and opiates are commonly used, whereas chronic pain treatment constitutes a special category where drugs like tricyclic antidepressants, anti-convulsants, gamma-amino butyric acid agonists, local anaesthetic analogs and NMDA antagonists are employed (5). The new GABA agonist anti-convulsant drugs increase the spectrum of the treatment and they represent the further steps with regards to the optimization of an individual’s therapy (6).

Opioid analgesics are the drugs of choice for the treatment of severe pain. While treating patients with persistent pain, it is of particular interest whether the antinociceptive effect of the analgesic Pharmacology Section persists after its repeated administration. But the use of opioids in chronic pain treatment has led to the development of tolerance and dependence after its repeated administration. To overcome the tolerance to the analgesic effects of morphine, higher doses are necessary for adequate pain relief, but these are often accompanied by an undesirable physical dependence and side effects such as constipation, nausea and respiratory depression (7). These problems limit the opioid dose and they result in inadequate analgesia. Therefore, non- opioid analgesics have been proposed to enhance the analgesic effect and to attenuate the side effects of opioids (8).

Hence, the present study was conducted to evaluate the synergistic anti-nociceptive activity of a GABA agonist with opioids in albino mice.

Material and Methods

This study was conducted in the Department of Pharmacology, Sri Ramachandra Medical College and Research Institute, Chennai, India. Prior permission was obtained from the institutional animal ethical committee.

Animals
Male Swiss albino mice (25-30g) were housed at the Animal House, Sri Ramachandra University under 12h: 12h light: dark cycles at a controlled temperature with free access to pellet feed (Gold Mohar Ltd., Bangalore) and water. The experimental protocol was approved by the Institutional Animal Ethical Committee. The animals were divided into different groups, with each group comprising of six mice (n = 6). Each animal were used once for the experiment.

All the observations were made between 9 AM and 12 noon. The experiment was conducted in a noiseless room, with a room temperature of about 29-31oC.

Drug and Dosage
All the drugs were obtained from the Ramachandra Hospital Pharmacy. They included Morphine, Tramadol Hydrochloride, Gabapentin, Baclofen, Tiagabine and Vigabatrine.

Nociceptive evaluation:

The hot – plate test:
The GABA agonist’s analgesia evaluation by using the acute pain model hotplate method was preferred in this study because all the four limbs and even the tail of the animal are stimulated simultaneously (9). Such heterotopic stimuli involving large body areas undoubtedly trigger diffuse noxious inhibitory controls with supraspinal origins (10),(11). So, it was decided that the nociceptive effect of the GABA agonists would be evaluated by using the hotplate method.

Before conducting the study, the Swiss albino mice were screened by sensitivity tests by placing the animals on the hot plate. Any animal that withdrew its hind paw or jumped in response in 5 seconds were rejected from the study. The animals were individually placed on a hotplate which was maintained at a constant temperature (52 ± 1oC). The latency to the first sign of paw licking or jump response to avoid heat nociception was taken as an index of the nociceptive threshold with a cut off time of 15 sec. The nociceptive threshold was observed 0, 30, 60, 90 and 120 min after the drug administration.

The percentage of the maximum possible effect (MPE) of the antinociception was calculated as follows (12):

% MPE = (Reaction time after treatment – Control reaction time)x 100 ∕ (Cut off time – Control reaction time)

Experimental design:
Before their administration, Morphine and Tramadol were dissolved in 0.9% saline. Gabapentin, Baclofen, Tiagabine and Vigabatrin were tablet powdered and dissolved in distilled water. These solutions were diluted to the required strength and they were given orally by using a gastric tube, 30 min before Morphine 1mg/kg s.c or Tramadol 10mg/kg i.p were given and the antinociceptive effect was evaluated.

Test – I Analgesia Evaluation of Morphine and Tramadol
Group 1 Saline 1mL/kg (i.p) - Control
Group 2 Morphine 1mg/kg (S.C)
Group 3 Morphine 3 mg/kg (S.C)
Group 4 Tramadol 10 mg/kg (i.p)
Group 5 Tramadol 20 mg/kg (i.p)

Test – II Analgesia Evaluation of Morphine with Gabapentin
Group 1 Morphine 3 mg/kg (S.C)
Group 2 Gabapentin 10 mg/kg (Oral)
Group 3 Gabapentin 30 mg/kg (Oral)
Group 4 Gabapentin 90 mg/kg (Oral)

Test – III Analgesia Evaluation of Morphine with Baclofen
Group 1 Morphine 3 mg/kg (S.C)
Group 2 Baclofen 4 mg/kg (Oral)
Group 3 Baclofen 6 mg/kg (Oral)
Group 4 Baclofen 10 mg/kg (Oral)

Test – IV Analgesia Evaluation of Morphine with Tiagabine
Group 1 Morphine 3 mg/kg (S.C)
Group 2 Tiagabine 0.4 mg/kg (Oral)
Group 3 Tiagabine 0.8 mg/kg (Oral)
Group 4 Tiagabine 1.6 mg/kg (Oral)
Group 5 Tiagabine 2.4 mg/kg (Oral)

Test –V Analgesia Evaluation of Morphine with Vigabatrin
Group 1 Morphine 3 mg/kg (S.C)
Group 2 Vigabatrin 7.5 mg/kg (Oral)
Group 3 Vigabatrin 15 mg/kg (Oral)
Group 4 Vigabatrin 30 mg/kg (Oral)
Group 5 Vigabatrin 45 mg/kg (Oral)

Test – VI Analgesia Evaluation Morphine with GABA Agonists
Group 1 Morphine 3 mg/kg (S.C)
Group 2 Gabapentin 10 mg/kg (Oral) and Morphine1mg/ kg (S.C)
Group 3 Baclofen 4 mg/kg (Oral) and Morphine 1mg/ kg (S.C)
Group 4 Tiagabine 0.4 mg/kg (Oral) and Morphine 1mg/ kg (S.C)
Group 5 Vigabatrin 7.5 mg/kg (Oral) and Morphine 1mg/ kg (S.C)

Test -VII Analgesia Evaluation Tramadol with GABA Agonists
Group 1 Morphine 3 mg/kg (S.C)
Group 2 Gabapentin 10 mg/kg (Oral) and Tramadol 10mg/kg (i.p)
Group 3 Baclofen 4 mg/kg (Oral) and Tramadol 10mg/kg (i.p)
Group 4 Tiagabine 0.4 mg/kg (Oral) and Tramadol 10mg/kg (i.p)
Group 5 Vigabatrin 7.5 mg/kg(Oral) and Tramadol 10mg/kg(i.p)

Results

Morphine
Two doses were studied; Morphine 3 mg/kg showed a significant analgesic effect, which was taken as the standard for the hot plate latency and the results were compared with those of all the test drugs which were used in this study.

Morphine 1mg/kg showed minimal anti-nociception. This dose, in combination with a low dose GABA agonist showed significant antinociception.

Tramadol
Two doses were studied; Tramadol 20 mg/kg showed a significant analgesic effect which was also somewhat similar to that of Morphine 3 mg/kg. Tramadol 10 mg/kg showed a minimal analgesic effect as that of Morphine 1mg/kg. The low dose Tramadol with a low dose GABA agonist in combination showed a significant analgesic effect as that of Morphine 3 mg/kg.

Gabapentin
Three doses were studied, 10mg (low dose), 30mg and 90mg and the results of these showed a dose dependent analgesic effect by using hotplate method. Gabapentin caused a dose dependent increase in the jumping or paw licking latency, which was significant at a 90 mg/kg dose level. This effect was comparable to that of Morphine 3 mg/kg.

Low dose Gabapentin 10 mg/kg (Low Dose) with Morphine 1mg/ kg (Low Dose) showed a significant analgesic effect as that of Morphine 3mg/kg. Low dose Gabapentin with Tramadol 10 mg/kg (low dose) showed a similar antinociceptive activity as that of Morphine 3 mg/kg.

Baclofen
Three doses were studied, 4mg (low dose), 6mg and 10 mg/ kg. The doses, 4mg and 6mg showed a minimal analgesic effect and Baclofen 10 mg/kg showed a significant analgesic effect. Baclofen showed a dose dependent analgesic effect and while it was given in higher doses, the animal showed sedation and muscle weakness.

Low dose Baclofen 4 mg/kg with Morphine 1mg/kg showed a significant anti-nociceptive effect as that of Morphine 3 mg/kg. Low dose Baclofen with Tramadol 10 mg/kg showed a significant antinociceptive activity which was similar to that of Morphine 3 mg/kg.

Tiagabine
Four doses were studied, 0.4 mg/kg, 0.8 mg/kg, 1.6 mg/kg and 2.4 mg/kg. Here, the doses, 0.4 mg/kg and 0.8 mg/kg showed no analgesic effect, but the higher doses of Tiagabine, 1.6 mg/kg and 2.4 mg/kg showed a minimal analgesic effect.

In case of a low dose combination, Tiagabine 0.4 mg/kg with Morphine 1mg/kg showed a significant anti-nociception which was similar to that of Morphine 3 mg/kg. Similarly, low dose Tiagabine 0.4 mg/kg with Tramadol 10mg/kg showed a significant antinociceptive activity as that of Morphine 3 mg/kg.

Vigabatrin
Four doses were selected, the doses, 7.5 mg/kg and 15 mg/kg showed no analgesic effect. The higher doses of Vigabatrin, 30 mg/kg and 45 mg/kg showed a minimal antinociceptive activity in a dose dependent manner.

Low dose Vigabatrin 7.5 mg/kg with Morphine 1 mg/kg in combination showed a significant analgesic effect which was almost similar to that of Morphine 3 mg/kg. Low dose Vigabatrin with Tramadol 10 mg/kg showed a similar antinociceptive activity as that of Morphine 3 mg/kg.

Discussion

Since anti-convulsants have been used for treating neuralgias, an interest has arisen to experimentally test the GABA agonists for their GABAergic mechanism of action of antinociception. Moreover, studies on Dextromethorphan and Midazolam alone or in combination have proven that they prevent the development of morphine induced tolerance and dependence. These effects can be related to the N-Methyl-D-Aspartate (NMDA) receptor antagonist behaviour of Dextromethorphan and the GABA-receptor agonist property of Midazolam (19). In this study, acute pain evaluation by using the GABA agonists, Gabapentin, Baclofen, Tiagabine and Vigabatrin were studied by using the hotplate method. This study has shown that a maximum analgesic effect is present only at the basal time measurement of the hotplate method.

Morphine two doses 1mg/kg and 3 mg/kg showed an analgesic effect peak at 60mts, which was found to extend upto 120mts (Table/Fig 5).

Similarly, Tramadol 10 mg/kg and 20 mg/kg showed a significant analgesic effect as compared to that of Morphine and also the antinociceptive effect was more prolonged than that of Morphine, which helped in avoiding frequent dosing (Table/Fig 6). The anti-nociceptive effect of Tramadol, in high doses, has shown a comparative effect with morphine in the hot-plate, formalin and the writhing analgesic models also (20).

Gabapentin is structurally related to GABA, a neurotransmitter that plays a role in pain transmission and modulation. Though Gabapentin does not bind to the GABA receptors, it has been shown recently, that it alters the release of GABA in the CNS (21). The administration of oral Gabapentin 300 mg before ambulatory laparoscopic surgeries decreases the postoperative pain, analgesic requirement and the nausea (22). Even though the real mechanism of action of these drugs was not known in this experiment, they showed a dose dependent, analgesic effect which could be compared to that of Morphine. Gabapentin caused a dose dependent increase in the jumping or paw licking latency, which was significant at a 90 mg/kg dose level (P<0.05). The effect started after 30 minutes of oral drug administration and it was maximum at 60 min. This effect was comparable to that of Morphine. The present study confirmed that Gabapentin had an analgesic action in an experimental acute pain model. A similar study was done on rats by Rakesh Dixit, et al., (15). He compared the analgesic effect of Morphine with that of Gabapentin by using the hotplate method. Gabapentin and Morphine, in a low dose combination, showed a significant analgesic effect and the animals which were tested were quite normal. A similar effect was seen with low dose Tramadol in combination with Gabapentin. Such effects were reported in another study wherein an oral premedication with 300 mg Gabapentin reduced the postoperative pain and total morphine consumption (23). Baclofen 4mg and 6mg did not exert an antinociceptive activity, while a higher dose, 10mg showed significant antinociception. Baclofen 4mg and 6mg did not produce motor incoordination, muscular hypotonia or ataxia. Baclofen 4mg and 6mg did not induce catalepsy, while a 10mg dose induced a state of mild sedation at 60min. A low dose combination with neither Morphine nor Tramadol, Baclofen 4mg did not have sedation.

A combination of low dose Morphine and low dose Baclofen showed a significant antinociceptive activity at 30 and 60 minutes. As both the drugs were in low doses, adverse effects were not seen. The animals were quite normal and there was no muscle weakness or sedation and they had a normal gait. The study by Cutting and Jordan (1975) reported that Baclofen exerted an antinociceptive activity and potentiate Morphine analgesia (24). A similar effect was seen with Tramadol 10mg in combination with and the analgesic effect was prolonged.

This study determined that Tiagabine, a GABA uptake inhibitor, created a hot-plate allodynia effect in mice, which was significant in a dose-dependent manner. Similar reports were available from Laughlin T.M, et al., 2002 (A comparison of the antiepileptic drugs tiagabine, lamotrigine, and gabapentin in mouse models of acute, prolonged and chronic nociception showed that gabapentin and lamotrigine produced antinociception in two mouse models of pain, an that an intra-thecal administration of tiagabine produced antinociception in all the three mouse models of pain) (17).

The higher the dose of Tiagabine, the animals were very active, while on testing, they showed only the jumping out of the hot plate effect. Low dose Tiagabine and Morphine showed a statistically significant antinociception. A similar effect was seen with Tramadol.

In this study, Vigabatrin showed a possible dose-dependent analgesic effect. A similar study was done by Alves ND; de Castro-Costa (1999) (a possible analgesic effect of vigabatrin in an animal experimental chronic neuropathic pain model) (18). A combination of low dose Vigabatrin and low dose Morphine showed a significant analgesic effect. Low dose Tramadol with low dose Vigabatrin showed a statistically significant analgesic effect as that of Morphine 3 mg/kg.

The low dose GABA agonists with low dose Morphine (Table/Fig 7) and the synthetic opioid derivative, Tramadol (Table/Fig 8) also showed a significant analgesic effect.

The behaviour of the animals was quite normal in this low dose combination. The adverse effects of the opioid were not noticed in this dose and also, the GABA agonist’s low doses did not have an analgesic effect; but in combination, it showed a significant anti-nociceptive effect and the adverse effect was expected to be minimal.

Tramadol appeared to produce less constipation and dependence than the equianalgesic doses of the strong opioids. Tramadol, in high doses, was found to increase the antinociception in mice, which is comparable to that of Morphine (20). The analgesic potency of Tramadol is about 10% of that of Morphine, following its parenteral administration. Tramadol provides postoperative pain relief which is comparable to that of Pethidine, and the analgesic efficacy of Tramadol can further be improved by its combination with a GABA agonist, as per the present study. The subcutaneous administration of Tramadol also can provide a local anaesthesia which is equal to Lidocaine, with a longer pain-free period after the operation (25).

In this study, acute pain evaluation by using the hotplate method showed that the GABA agonists, Gabapentin, Baclofen, Tiagabine and Vigabatrin all had an anti-nociceptive effect in a dose-dependent manner. Even though these drugs had an anti-nociceptive effect individually, their clinical long term use and their adverse effects are yet to be studied. The combination of low dose Tramadol with a low dose GABA agonist showed a statistically significant antinociception and the effect was also sustained. Similar synergic studies of Gabapentin with Morphine which were done by Manzumeh-Shamsi Meimandi, et al., (2005) revealed an increased analgesic effect by the tail flick test. These results showed a less frequent dosing for chronic pain and lesser adverse effects than both groups of drugs individually (26).

Conclusion

All the GABA agonists which were used in this study (Gabapentin, Baclofen, Tiagabine and Vigabatrin) had an analgesic effect in a dose dependent manner. But the use of these drugs as analgesics for a long term clinical use for severe pain needs further studies.

Combinations of low dose GABA agonists with low dose Morphine or Tramadol showed a very good analgesic effect in mice. Tramadol has less adverse effects than Morphine and so, the low dose GABA agonists and Tramadol in a low dose combination can be tried for chronic or severe pain, but this needs further clinical trials to prove it.

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DOI and Others

ID: JCDR/2012/4105:0034

Date Of Submission: Feb 04, 2012
Date Of Peer Review: Mar 03, 2012
Date Of Acceptance: Mar 26, 2012
Date Of Publishing: May 31, 2012

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