This document discusses a study on the effect of tramadol dependence and abstinence on the immune system in Egyptian male patients. The study found that abstaining from tramadol for 6 months decreased IgA, IgM, and IL-6 levels and increased IL-2 levels. Patients prescribed naltrexone had higher IgA levels after 3 months of abstinence. The study concluded that tramadol dependence may impair immune function, but naltrexone did not significantly affect immune markers. However, the study had limitations including a small sample size and lack of control over nicotine use.

3. By
Ehab Hassan Elbaz
M.B.B.Ch., M.Sc. of Neuropsychiatry
EFFECT OF TRAMADOL
DEPENDENCE ON THE IMMUNE
SYSTEM IN A SAMPLE OF EGYPTIAN
MALE PATIENTS

4. Prof. Mohamed Hamed Ghanem
Professor of Psychiatry
Faculty of Medicine - Ain Shams University
Prof. Amany Haroun EL-Rasheed
Professor of Psychiatry
Faculty of Medicine - Ain Shams University
Prof. Abeer Mahmoud Eissa
Professor of Psychiatry
Faculty of Medicine - Ain Shams University
Prof. Mohamed Reda Abd Elraoof
Professor of psychiatry
Military Medical Academy – Egyptian Armed Forces
Dr. Ahmed Nabeeh Agam
Head of the Laboratory Department
Maadi Armed Forces Hospital
SUPERVISION

5. AKNOWLEDGMENT

7. The nonmedical use of opioid analgesics has a
great burden to our society as manifested in the
physical and psychological consequences of
addiction and the effect of illicit use on
physicians’ prescribing habits.
The financial burden associated with such
misuse and abuse is significant, especially when
factors as associated health care, workplace
costs and the cost of treatment for patients with
opioid addiction are considered.
INTRODUCTION

8.  Tramadol was introduced as a non-scheduled drug on the market in
the UK in 1994 and in the USA in 1995 for treatment of moderate
to moderately severe pain.
 It was first synthesized in 1962 and has been available in Germany
since 1977. As a centrally acting analgesic, tramadol is atypical
because it produces analgesia through both mu opioid and
monoamine actions.
 Based on analgesic studies, tramadol is thought to be
approximately one-tenth as potent as morphine when each is
administered parenterally and approximately one-third as potent
when each is administered orally.
(David et al., 2006)
INTRODUCTION (CONT.)

9.  An increasingly alarming phenomenon of Tramadol abuse has been
heavily demonstrated in the Egyptian community in the last years.
 Though the issue of drug abuse is not new to Egyptian society,
tramadol is associated with a wide range of abuse and illegal
transactions that made it easily accessible and readily provided at
cheap cost.
 The alleged usages of tramadol contributed greatly to its popularity
and massive use especially among youth and middle- aged groups as
a remedy for premature ejaculation and for extended orgasm and to
increase sexual pleasure as promoted in many online drug stores
and media.
(Fawzi, 2011)
INTRODUCTION (CONT.)

10.  The idea that opioids suppress the immune system and lower resistance to
infections is not new. There is evidence that opioids modulate both innate and
acquired immune responses.
 Acute and chronic administration of opioids is known to have inhibitory effect on
humoral and cellular immune responses including antibody production, natural
killer lymphocyte activity, cytokine expression and phagocytic activity.
 Not all opioids induce the same degree of immunomodulatory effects. From
reviewing the literature, it is evident that the majority of studies investigating
the effects of opioids on the immune system have been conducted in animals.
 From these animal studies conclusions have been drawn that opioids can be
divided into those that are immunosuppressive, such as codeine, methadone and
morphine . And those that are less immunosuppressive, including buprenorphine,
hydromorphone, oxycodone and tramadol.
(Paola Sacerdote, 2006)
INTRODUCTION (CONT.)

11. Few studies had examined the effect of tramadol
abuse on the immune system and to our
knowledge no Egyptian studies are conducted in
this field , and whether the treatment from
tramadol dependence restore the normal
function of the immune system or not is not well
understood .
RATIONALE OF THE STUDY

12. AIM OF THE WORK

13. 1. To determine the effect of tramadol dependence on the
immune system function.
2. To determine the effect of abstinence from tramadol
dependence on the immune system.
3. To determine the effect of the opioid antagonist naltrexone on
the immune system
AIM OF THE WORK

14. SUBJECTS AND METHODS

15. Study design:
 A prospective interventional study.
Site of the study:
 The study was carried out in the addiction treatment unit in Maadi Military
Hospital in Cairo.
 The laboratory investigations were carried out in Maadi Military Hospital
laboratory and in the Armed Forces Laboratories for Medical Investigations and
Blood Banks in Cairo.
SUBJECTS AND METHODS

16. Ethical approval:
 The study protocol was approved by the ethics
committee of faculty of medicine, Ain Shams University.
SUBJECTS AND METHODS (CONT.)

17.  Selection of cases:
 A sample of 61 cases was selected by convenient
sampling from patients seeking treatment from tramadol
dependence and willing to be admitted to the inpatient
facility in the addiction treatment unit according to the
following inclusion and exclusion criteria:
SUBJECTS AND METHODS (CONT.)

18. Inclusion criteria:
- Age : 18 – 60 years
- Sex : male
- Education : at least secondary school
- No history of heroin injection
- Tramadol is the main drug of abuse
- Duration of Tramadol dependence is at least one year
- No history of any chronic medical condition
- Has a stable home address and a close relative who supervised the patient
compliance with the visit schedule and study procedures
SUBJECTS AND METHODS (CONT.)

19.  Exclusion criteria:
- Age below 18 and above 60 years.
- Polysubstance abuse.
- History of any medical condition affecting the immune system.
- History of chronic liver or renal disease.
- Presence of DSM – IV axis I diagnosis.
- History of hypersensitivity to naltrexone.
- Elevated liver enzymes 3 times or more than the normal levels.
SUBJECTS AND METHODS (CONT.)

20.  Drop out:
- If a patient misses an appointment, a phone call was made to the
patient or his relatives to clarify the reason, and if appropriate
,he was asked to be interviewed in less than a week and a drug
screen was made, otherwise he was excluded from the study.
- If the patient missed two successive appointments or more
without appropriate reason, he was excluded from the study.
SUBJECTS AND METHODS (CONT.)

21. Procedures:
 All patients subjected to the following procedures at time of admission:
 1. Written informed consent.
 2. Past medical history and complete physical examination.
 3. Psychiatric tools:
 a- Structured Clinical Interview for DSM IV Axis-I Disorders (SCID-I).
 b- Structured Clinical Interview for DSM IV Axis-II Disorders (SCID – II).
 c- Addiction Severity Index (Arabic Version).
 4. Laboratory tests:
 a- Complete blood count (CBC).
 b- Liver function test (SGOT, SGPT).
 c- Renal function tests (serum urea and creatinine).
 d- Random blood sugar.
 e- Assay of Hepatitis B,C and AIDS.
 f- Toxicology screening.
 g- Serum immunoglobulin concentrations (IgG, IgA, and IgM).
 h- Measurement of serum interleukin 2 and interleukin 6.
SUBJECTS AND METHODS (CONT.)

22. After completion of the detoxification period
and disappearance of the withdrawal symptoms
and after two consecutive negative urine
samples patients randomized into two groups,
one received naltrexone 50 mg orally once per
day for the rest of the study and the other group
not.
SUBJECTS AND METHODS (CONT.)

23.  After discharge from the hospital, patient followed up once every
week for 3 months and urine toxicology done every time. After
that, patients followed up every 2 weeks until the end of the study
(6months).
 After 3 and 6 months from the start point, the patient group
examined for the following laboratory investigations:
1. Complete blood count ( CBC )
2. Liver function test ( SGOT, SGPT)
3. Renal function tests ( serum urea and creatinine )
4. Serum immunoglobulin concentrations (IgG, IgA, and IgM)
5. Measurement of interleukin 2 and interleukin 6
SUBJECTS AND METHODS (CONT.)

24. RESULTS

25. COMPARISON BETWEEN NALTREXONE-FREE AND
NALTREXONE-PRESCRIBED GROUP ACCORDING TO ASI
SEVERITY PROFILE
There was a statistically significant difference between the 2 groups in the
medical, occupational and drug aspects of ASI , with the naltrexone-free
patients worse on all these aspects

26. COMPARISON BETWEEN NALTREXONE-FREE AND
NALTREXONE-PRESCRIBED GROUP REGARDING THE
IMMUNOLOGICAL PARAMETERS AFTER 3 MONTHS
There was a statistically significant difference (P<0.05) between the 2 groups in the
level of IgA after 3 months, with the naltrexone-prescribed group showing higher
levels of IgA.
Naltrexone-free Naltrexone- prescribed

27. COMPARISON BETWEEN NALTREXONE-FREE AND
NALTREXONE-PRESCRIBED GROUP REGARDING THE
IMMUNOLOGICAL PARAMETERS AFTER 6 MONTHS
There was a statistically significant difference (P<0.05) between the 2 groups in the
level of IgA after 6 months, with the naltrexone-prescribed group showing higher
levels of IgA.
naltrexone-prescribednaltrexone-free

28. DIFFERENCE IN THE LEVEL OF ( IgA) OVER THE 6
MONTHS PERIOD
There was a highly statistically significant difference over the periods through IgA in
the naltrexone-free, naltrexone-prescribed group and total patients.

29. THE DIFFERENCE IN THE LEVEL OF (IgM )OVER THE 6
MONTHS PERIOD
There was a high statistically significant difference in the level of IgM over the
6 months period in the naltrexone-free, naltrexone-prescribed and total
patients.

30. THE DIFFERENCE IN THE LEVEL OF( IgG) OVER THE 6
MONTHS PERIOD
There was no statistically significant difference in the level of IgG over the 6
months.

31. THE DIFFERENCE IN THE LEVEL OF IL-2 OVER THE 6
MONTHS PERIOD
There was a highly statistically significant difference over the periods through
IL-2 .

32. THE DIFFERENCE IN THE LEVEL OF IL-6 OVER THE 6
MONTHS PERIOD
There was a statistically significant difference over the periods through IL-6
in the naltrexone-prescribed group and total patients.

33. CONCLUSION

34.  Abstinence from tramadol dependence for 6 months has effects
on some of the immunological parameters being studied in the
current study in the form of:
1.Decrease in the serum level of IgA and IgM
2.Increase in the serum level of IL-2
3.Decrease in the serum level of IL-6
4.No change in the serum level of IgG
CONCLUSION

35.  The use of naltrexone 50 mg orally as an opioid
antagonist in patients with tramadol dependence for 6
months seems to have no effects on the immunological
parameters studied in the current study.
 The use of naltrexone 50 mg orally in patients with
tramadol dependence for 3 months may increase the
serum level of IgA.
CONCLUSION (CONT.)

36. LIMITATIONS

37.  The relatively small size of the sample, which is convenient
sample and being a single-center study suggesting that it
may not be representative of tramadol dependent patients
in Egypt.
 While the inclusion criteria for age are from 18 – 60 years,
the range of age in the sample was from 21- 43 years, which
may indicate a relative narrow age group.
 All the sample population was males only and the results is
not representative to all the general population.
LIMITATIONS

38.  The difficulty in controlling the nicotine dose and use
among the addicts may has an effect over the serum
level of the immunological parameters.
 Another limitation of our study is the presence of
polysubstance pattern in the drug history that may
affect the levels of the immunological parameters
 The use of some psychotropic medications by some
patients may represent a potential confounding factor.
LIMITATIONS (CONT.)

39. Strength:
 Despite these limitations, the current study represents
the first study of the immune functions in tramadol
dependent patients in Egypt that may guide future
research in this area.
LIMITATIONS (CONT.)

40. RECOMMENDATIONS

41.  Clinical recommendations:
 Psychiatric assessment with patients with tramadol
dependence should include a detailed history about
symptoms of the probability of immune system
dysfunction.
 Clinicians should be aware that during early period of
abstinence from tramadol dependence the immune
system functions is impaired with high possibility of
opportunistic infections.
RECOMMENDATIONS

42.  Research recommendations:
 Further studies are recommended to clarify the effect of
tramadol dependence on other types of interleukins and
other immune function indicators.
 Future research including female tramadol dependence and
comparing the effects on the immune functions between
male and female.
 Further studies are needed on a wider population sample to
confirm the results and be able to generalize it on patients
with tramadol dependence.
RECOMMENDATIONS (CONT.)

43.  Community recommendations:
A. Media recommendations:
 Psychoeducation and awareness campaigns about the dependence
nature of tramadol and its effects on mind and body
 Counteract the myth that tramadol increase the energy and improve
work performance.
B. Legal regulations:
 Including tramadol with other substance of abuse in the routine drug
screening in the workplace.
RECOMMENDATIONS (CONT.)