1. به نام خداوند جان و خرد كزو برتر انديشه بر نگذرد
Opioids Withdrawal
Diagnosis & Management
Dr Gholam Reza Kheirabadi
Assistant Professor of psychiatry
Isfahan University of Medical Sciences

2. Addiction and Dependence
Drug addiction: is a condition in which an individual has lost the power of self-control with reference to a drug and abuses the drug to such an extent that the individual, society, or both are harmed.
Dependence: refers to a state resulting from habitual use of a drug, where negative physical withdrawal symptoms result from abrupt discontinuation.
The key is that addiction results when the reward pathways in the brain are stimulated by drug use thereby causing dependence due at least in part to psychological reasons.
Dependence implies need of the drug to avoid withdrawal symptoms, not to gain a reward response in all cases. Palliative care patients do not experience a “high” when taking an opioid and are therefore not considered to be addicted.

3. Tolerance
Tolerance, describes the need for a drug user to administer larger and larger doses of the drug to achieve the same psychoactive effect.
When the body's chemical equilibrium is upset, as in habitual drug-taking, the body sets up oppositional processes to restore itself. More of the drug is needed to overcome these efficient corrective processes.
While considerable debate exists about the mechanisms of opioid tolerance, two factors have been isolated with a degree of certainty.
Receptor Downregulation- Opioid receptors in the body are actively reduced due to overexposure to opioids. This can also have an effect on endogenous opioid peptide function (i.e. regular functioning of endorphins)
Antiopiates- Chemicals like neuropeptide FF, orphanin FQ/nociceptin, and Tyr-W-MIF-1 have all been found to block the function of opioids. This activity is due to the fact that these drugs can block g-protein activity.

4. Opioids produce their effect by acting at the opioid receptors in the nervous system
-opioid receptor most important
Agonists
bind to the receptor and stimulate physiological activity
Partial agonists
bind to the receptor but do not produce maximum stimulation
Antagonists
have no intrinsic pharmacological effect, but bind to the receptor and can block the action of an agonist

6. Opioid effects & withdrawal
Opioid effects Opioid withdrawal
Analgesia
Sedation
Euphoria
Pinpoint pupils
Low BP, PR, RR
Dry skin, mouth, ↑urine
Constipation, ↑bowel action
Nausea, vomiting

7. Source: NSW Department of Health (2007) NSW Drug and Alcohol Withdrawal Clinical Practice Guidelines

8. Dependence (DSM IV-TR)
 3 occurring at any time in the same 12 month period:
Tolerance
Withdrawal
Opioids taken in larger amounts or longer than intended.
Persistent desire or unsuccessful attempts to cut down or control use.
A great deal of time is spent in activities necessary to obtain opioids, use opioids, or recover from their effects.
Important social, occupational, or recreational activities are given up or reduced because of opioid use.
Opioid use is continued despite knowledge of harms caused or exacerbated by opioids.

9. Factors affecting drug abuse & dependence
User
Environment

10. Withdrawal Management
(Detoxification)

11. Role of assessment Assessment serves two key functions:
To ascertain valid information in order to identify the most suitable management plan;
To engage the patient in the treatment process
Establishing rapport with the patient
Facilitating treatment plans

12. Stages of change model
Pre-contemplation: People do not have major concerns regarding their drug use and are not interested in changing behaviour
Contemplation: People aware that there are both benefits and problems arising from their drug use, and are weighing up whether or not to make changes - or what those changes should be
Action: People are implementing strategies in order to change
Maintenance: holding onto the behaviour changes
Relapse: can be volitional, or triggered by physical, emotional, social factors

13. Some authors recognise a preparation stage before the action stage
RELAPSE
MAINTENANCE
&
Detoxification
ACTION
CONTEMPLATION
A version of this diagram will be included in the online publication: Proude et al (2009) The Treatment of Alcohol Problems
A Review of the Evidence. Commonwealth Department of Health and Aging, Canberra.
Some authors recognise a preparation stage before the action stage
In this diagram the pre-contemplation stage is merged with relapse
Proude, E (2009), unpublished data

14. Principles of effective treatment
Long duration of treatment
Adequate dose of medication
Quality of therapeutic relationship
Psycho-social supports for the patient
Regular review, supervision & monitoring
Participation in counselling
Environment, family, friends, employment
Bio-psycho-social model for chronic condition

15. Methadone Full agonist at - opioid receptor
Onset min after dose, Peak after ~ hrs
Long-acting: t1/2= hrs: one dose / day
Opioid toxicity with too much methadone: sedation, respiratory depression, death
1 dose of 20-40mg can kill child
Repeated doses of 30–40mg can kill an adult (opiate naïve)
1 dose of 70mg can kill an adult (opiate naïve)
Widespread diversion & methadone related deaths where no supervision (e.g. UK)
Daily supervised dispensing at clinics / pharmacies
Henry-Edwards et al (2003) Clinical Guidelines and Procedures for the Use of Methadone in the Maintenance Treatment of Opioid Dependence. Commonwealth Government of Australia, Canberra.
Henry-Edwards et al (2003) Clinical Guidelines and Procedures for the Use of Methadone in the Maintenance Treatment of Opioid Dependence.

16. Principles of methadone dosing
Induction
Require slow induction (‘start low & go slow’)
20-30mg / day & increase dose by 5-10mg every 1-3 days until reach target dose (over 2-6 weeks)
Maintenance
Doses of 20 – 40mg prevent opiate withdrawal
Doses >60mg most effective in reducing heroin use
Withdrawal
Gradual dose reductions (at rate of 10mg / month)
Henry-Edwards et al (2003) Clinical Guidelines and Procedures for the Use of Methadone in the Maintenance Treatment of Opioid Dependence. Commonwealth Government of Australia, Canberra.
Henry-Edwards et al (2003) Clinical Guidelines and Procedures for the Use of Methadone in the Maintenance Treatment of Opioid Dependence.

17. MEHTADONE Stabilization on Methadone: -Initial dose:
A:10-20mg→ if withdrawal persist → Repeat the dose( 2 hours later ) [ no more than 40mg during first day].
B: Calculation of equivalent withdrawal suppressing dose of methadone?
(Methadone is 3time potent than morphine).
C: Add 10mg/2-3day or week( different for outpatient V.S inpatient detoxification?)
up to final stabilization(more gradual and upper final dose in outpatient setting).

18. Buprenorphine Partial agonist at the  opioid receptor
- Low intrinsic activity only partially activates receptors
High affinity for the  receptor
Binds more tightly to receptors than other opioids
Developed in 1980s as analgesic

19. Safety Aspects of BPN Less risk of overdose c/w full opiate agonists
Less respiratory depression & sedation than methadone
BPN ‘tolerated’ by individuals with low levels of opiate dependence
Sailing effects
Potential concerns re: safety
BPN related deaths reported in combination with other sedatives (EtOH, BZDs) … BUT less of a concern than other opiates (e.g. methadone, heroin)

20. Clinical Pharmacology
Sublingual tablets
0.4, 2 & 8 mg tablets available
3 to 10 minutes to dissolve
Time course
Onset: 30–60 min, peak: 1–4 hours
Duration of action dose-related (1 dose / day)
Side effects
Typical for opioid class: less sedating than methadone
Withdrawal syndrome
Milder than full agonists
Lintzeris et al (2006) National clinical guidelines and procedures for the use of buprenorphine in treatment of opioid dependence. Commonwealth Government of Australia, Canberra.
Lintzeris et al (2006) National clinical guidelines and procedures for the use of buprenorphine in treatment of opioid dependence.

21. Overview BPN Doses Induction
Delay first dose of BPN until early opiate withdrawal
Commence 4 to 8 mg daily
Frequent & rapid dose increases possible (by 2 to 8mg/day)
Maintenance
Daily doses: 8 – 16mg (max 32mg) required initially
Alternate day dosing possible for many clients
Withdrawal
More rapid dose reductions possible than methadone
(e.g. 2 – 4 mg / week usually well tolerated)
Lintzeris et al (2006) National clinical guidelines and procedures for the use of buprenorphine in treatment of opioid dependence. Commonwealth Government of Australia, Canberra.
Lintzeris et al (2006) National clinical guidelines and procedures for the use of buprenorphine in treatment of opioid dependence.

22. Buprenorphine-naloxone tablet (Suboxone®)
Sublingual tablet in 4:1 ratio (BPN:NLX)
Naloxone (antagonist) poorly absorbed sublingually & inactive
Naloxone produces antagonist (withdrawal) effects if tablet injected by heroin user
Enables take-away doses with greater convenience for patients & less risk of tablet misuse

23. Tramadol
Mechanism: serotonin & nor-epinphrin reuptake inhibitor(Parent compound) + µ agonist(metabolize compound-desmethyltramadol).
Withdrawal control with mg for modest and 600 mg for sever withdrawal)
Seizure in high doses CNS suppressant Using with B.Z & seretonergic syndrome with SSRI.

24. α2 Agonists
- Clonidine
-Lofexidine (Less Hypotensive)

25. Mechanism & Sideffects
It has specificity towards the presynaptic alpha-2 receptors in the vasomotor center in the brainstem. This binding decreases presynaptic calcium levels, and inhibits the release of norepinephrine (NE). The net effect is a decrease in sympathetic tone
This drug may cause drowsiness, lightheadedness, dry mouth, dizziness, or constipation. Clonidine may also cause hypotension. It can also cause inhibition of orgasm in women

26. Clonidine
Patient stabilized on low dose of opioids (30 – 40 Methadone/ day).
starting dose 0/1 – 0/3.
*Maximum dose (1/mg/day) In outpatient & mg/day In hospitalized patients.
*Adjusting Dose based On Hypotension & sedation.
Contraindication: acute or chronic cardiac disease, Renal & metabolic disease, Hypotension).

27. Clonidine More effective in: =stabilization on Methadone.
=good Relationship with therapist.
Effective in suppressing of : Sweating, cramps, nusea, vomiting and diarrhea
Ineffective In suppressing of (Muscle aches – Lethargy – Insomnia – restlessness and Craving).
Non – effective on relapse after complete detoxification.
Facilitation of detoxification of Methadone Maintained patients & subsequent stabilization on naltrexone.

28. When should we stop substitution treatment?
Chronic condition needs long term treatment
Premature cessation of treatment usually results in relapse to dependent heroin use
Consider ending treatment when:
No illicit drug use for months / years
Stable social environment
Stable medical / psychiatric conditions
Patient ‘has a life’ that does not revolve around drugs
Patient informed consent
When do we stop anti convulsants/antidepressants?