الفهرس 
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Abstract
Introduction
Tramadol is a centrally acting analgesic with a multimode of action. It acts on serotonergic and noradrenergic nociception, while its metabolite O-desmethyltramadol acts on the μ-opioid receptor. Its analgesic potency is claimed to be about one tenth that of morphine. Tramadol action appears to be produced in a multimodal mechanism involving the μ-opioid system, the noradrenergic system, and the serotonergic system (Minami, et al. 2006).
Tramadol has low abuse potentiality. The nature of tramadol as a mixed opioid agonist acting on μ receptor with agonist effect on adrenergic alpha 1 receptors suggests the dependence potentiality of tramadol. Low affinity to opioid receptors explains its low abuse potentiality (Lanier, et al. 2010).
Being a narcotic analgesic with effect on serotonin, norepinephrine receptors and dopamine reward system, tramadol was expected to have an impact on cognition and memory which act through the same neurotransmitters and the same pathways (Miriam, et al. 2010).
In this study we hypothesized that tramadol causes impairment in cognitive functions and these impairments are reversible after abstinence from tramadol and we have tested the hypothesis on 3 groups of samples. The study consisted of two parts; theoretical and practical part:
A. Theoretical Part
It included the review of literature divided into the following chapters:
Chapter I: Epidemiological studies on substance abuse in Egypt and worldwide.
It includes: epidemiological data, substance abuse epidemiological studies in Egypt, trend of opiate use in Egypt and history of medical use of tramadol and abuse in Egypt.
Chapter II: Clinical pharmacology of tramadol.
This chapter discussed psychopharmacological items and side effects of tramadol as follow: Pharmacodynamics, Pharmacokinetics, indications & contraindications of tramadol, adverse reactions of tramadol, the most serious side effects of tramadol, its Interactions with other drugs, its dependence and abuse potential and its current international controls and current and past national controls
Chapter III: Neurocognitive effects of opioids.
This chapter reviews the cognitive effects of opioids including cognitive effects of tramadol.
Chapter IV: Management of patients with tramadol dependence with special emphasis on cognitive dysfunction.
This chapter reviews treatment of cognitive dysfunction in tramadol abuse, pharmacological treatment of the opioid dependence, psychological rehabilitation of opioid dependence, drug policy in Egypt and Current treatment practices.
B. Practical Part
• Hypothesis
1. The hypothesis to be tested in this study is that long term tramadol abuse may affect cognitive functions.
2. Abstinence from tramadol reverses the cognitive impairments.
• Aim of the work
The aim of this study is to:
1. Study the effect of tramadol addiction on cognitive functions.
2. To determine if cognitive impairment caused by tramadol is reversible or not.
2. Study the impact of other related factors as duration of intake and dose of tramadol on cognition.
• Study design:
The study is an observational, case-control and cross-sectional study aiming at assessment of the cognitive functions in tramadol dependent patients.
• Sample
This study compares between three groups regarding cognitive functions. The first group is composed of 30 patients with two years or more of regular tramadol abuse (Dependency). The second group is composed of 30 patients who are abstinent from tramadol intake for three months to six months (early recovery stage). The third group is a control group of 30 persons from relatives of the first and second group who are matched with them regarding age and educational level. Convenient sample will be recruited from Kasr Al-Aini psychiatric and addiction hospital (from outpatient clinic and inpatient admitted patients).
• Inclusion criteria
1. Patients fulfill criteria for the diagnosis of tramadol dependence based on DSM-5 criteria.
2. Age from 18:50 years.
3. Those who can read and write.
• Exclusion criteria
1. Patients with other substance related or addictive disorders.
2. Patients with comorbid psychiatric disorder that may affect cognition.
4. General medical condition that may affect cognition e.g. DM, HTN, Parkinson’s disease, Huntington’s disease, etc.
• Tools
Each patient in the study was subjected to the following:
A. Psychiatric interview:
Using semi structural interview derived from Kasr Al-Aini Sheet with special emphasis on age, occupation, marital status, socioeconomic status and substance history including age of onset, dose, duration, causes of intake and side effects (including any seizures during intake or withdrawal).
2. Physical examination Including temperature, blood pressure, pulse, heart, chest and abdominal examination to exclude general conditions that may affect cognition.
3. Routine neurological examination:
Standardized neurological examination.
4. Liver and kidney functions and random blood sugar.
5. Urine toxicological screen for Tramadol, Cannabinoids, Benzodiazepines and Opioids to exclude effect of other substances on cognition.
6. Addiction Severity Index Scale (McLellan, et al.
1992). Arabic version (Qassem, et al. 2003).
7. To assess cognitive functions:
A. Montreal cognitive assessment (MoCA) (Nasreddine, et al. 2005). Arabic version (Rahman and El Gaafary, 2009). The Arabic version of MoCA as a prominent tool for evaluation of MCI. The MoCA test is a one-page 30-point test administered in approximately 10 minutes. Each participant had the test individually. It was used to assess several domains of cognition such as the short-term memory recall task (5 points) involves two learning trials of five nouns and delayed recall after approximately 5 minutes. Visuospatial abilities are assessed using a clock-drawing task (3 points) and a three-dimensional cube copy (1 point). Multiple aspects of executive functions are assessed using an alternation task adapted from the trail-making B task (1 point), a phonemic fluency task (1 point), and a two-item verbal abstraction task (2 points). Attention, concentration and working memory are evaluated using a sustained attention task (target detection using tapping; 1 point), a serial subtraction task (3 points), and digits forward and backward (1 point each). Language is assessed using a three-item confrontation naming task with low-familiarity animals (lion, camel, rhinoceros; 3 points), repetition of two syntactically complex sentences (2 points), and the aforementioned fluency task. Finally, orientation to time and place is evaluated (6 points).
Normal MoCA score is above 25, scores of 25 or less are affected.
B. Trail making test (TMT) (Reitan, 1958). Part A requires the individual to draw lines to connect 25 encircled numbers distributed on a page. Part A tests visual scanning, numeric sequencing, and visuomotor speed. Part B is similar except the person must alternate between numbers and letters and is believed to be more difficult and takes longer to complete. Part B tests cognitive demands including visual motor and visual spatial abilities and mental flexibility. Both sections are timed and the score represents the amount of time required to complete the task by seconds.
• Results
The present study shows:
1. Tramadol addiction causes cognitive impairment as shown by its effect on total MoCA scores in both patients who are still taking tramadol or those who are abstinent for 3 to 6 months. As regard the subscores of MoCA; we found statistically important impairment in verbal fluency and short-term memory in both groups of patients in comparison with the control group.
2. No effect of daily dose of tramadol on cognitive performance.
3. No effect of duration of dependence on tramadol on cognitive performance.
Conclusion
Tramadol addiction causes cognitive impairment; mainly verbal fluency and memory impairment.
Abstinence from tramadol for 3 to 6 months did not reverse these cognitive impairments.
No effect of daily dose of tramadol on cognitive performance.
No effect of duration of dependence on tramadol on cognitive performance.
Recommendations
Clinical
• Patients with tramadol addiction should routinely be asked about symptoms suggestive of cognitive impairment prior to treatment and at regularly scheduled follow-up visits.
• Rehabilitation programs should stress on improving cognitive functions by cognitive training and pharmacological methods.
Research
• Include larger sample size.
• Include female patients.
• Assessment of cognitive functions after longer period of tramadol abstinence to determine if the cognitive impairments are reversible or not.
• Use of more detailed assessment tools for more accurate assessment of certain cognitive domains.
• Encouragement of Arabic translation and validation of various assessment tools used in substance use disorders and assessment of cognition.
• Further studies and researches are needed to address the prevalence and epidemiology of tramadol use in Egypt.
Community
• Further awareness campaigns and psychoeducation about tramadol dependence in school age and college students and modifying the belief about tramadol use as a stimulant to give more energy and concentration about their academic achievement and addressing the different consequences of tramadol abuse.
• Increase awareness of tramadol use as a substance of abuse through the media and correction of myths about its use for a sex and energy enhancer.
• Strict application of Drug control policy.
STUDY LIMITATIONS
1. The relatively small sample size in addition to the demographic characteristics limits the generalization of the results to different populations.
2. This is a Case-control study which is observational in nature and thus do not provide the same level of evidence as randomized controlled trials. The results may be confounded by other factors.
4. Some participants in patient group were under psychotropic medications e.g. antipsychotic, antidepressants and mood stabilizer that represent a potential confounding factor. However, for ethical reasons medications could not be stopped for patients who joined the study.
5. Inability to identify the accurate dose of tramadol may affect the results.