CURRICULUM VITAE

Prof.Dr.dr.Samekto Wibowo, P.Far.K.,Sp.FK.,Sp.S(K)

• Lahir : Klaten 16 Maret 1946
• Pekerjaan : Dosen /dokter
• Alamat : Sapen GK I /621 Yogyakarta
• Status : Menikah, 2 anak, 7 cucu
• Riwayat Pendidikan
- SR/SD : SR Gemolong – SRL I Surakarta (lulus 1957)
- Sekolah menengah : SMP III Surakarta (lulus 1960)
SMA I Surakarta (lulus 1963)
- Kedokteran : FK - UGM lulus 1970
- Farmakologi : FK – UGM / UNAIR (Brevet 1975)
- Neurologi : FK – UGM : Spesialis 1987
- S3 : UGM : lulus 1998
• Riwayat Jabatan / pekerjaan
Farmakologi 1967 – 1982
Neurologi 1982 – sekarang
Guru Besar 2000
• BUKU
1. Samekto Wibowo,Abdul Ghofir : Farmakoterapi dalam Neurologi (2001)
2. Samekto Wibowo,Abdul Ghofir : Obat Antiepilepsi (2007)
3. Samekto Wibowo, Abdul Ghofir: Disfungsi Ereksi (2007)
OPIOID IN THE MANAGEMENT
OF CHRONIC PAIN
NO FEAR OF ADDICTION

Samekto Wibowo
Dept of Neurology, Fac of Medicine UGM
Sardjito General Hospital
Yogyakarta
Natural opium alkaloids

Morphine - gold standard

Codeine
Thebaine - (non-analgesic)
 Physicians’ Dilemma and Challenge

To prescribe

Not to
prescribe

Know, monitor, and balance use

© AMSP 6
• Opioid use is generally save for most patients, but may be associated
with adverse effects
• The most serious effect being respiratory depression, which is
generally preceded by sedation
• Others: dizziness, nausea, vomiting, constipation, sedation, delirium,
hallucination, falls, hypotension, and aspiration pneumonia
• Problems: underprescribing, overprescribing, tolerance, dependence,
drug abuse
• Prescription of opioids for chronic, intractable pain is appropriate
when more conservative methods are ineffective and the treatment
plan is reasonable
• Treatment plan tailored to the needs of the patient, and minimization
of adverse effects, and on going monitoring and documentation
• However, legislation and regulatory policies should not discourage or
prevent prescription of opioids where medically indicated and
appropriately managed
History of Opioids
• Opium is extracted from poppy seeds (Paper somniforum)
• Used for thousands of years to produce:
• Euphoria
• Analgesia
• Sedation
• Relief from diarrhea
• Cough suppression
 OPIUM
“Among the remedies
which it has pleased
almighty God to give
man to relieve his
sufferings, none is so
universal and so
efficacious as opium”
Sir Thomas Sydenham 1680

Opioid is selectiively eliminate suffering

from pain. Don’t damage organ.
History cont’d
• Used medicinally and recreationally from early Greek and Roman
times
• Opium and laudanum (opium combined with alcohol) were used to
treat almost all known diseases
• Morphine was isolated from opium in the early 1800’s and since then
has been the most effective treatment for severe pain
Pharmacological Effects
• Sedation and anxiolysis
• Drowsiness and lethargy
• Apathy
• Cognitive impairment
• Sense of tranquility
• Depression of respiration
• Main cause of death from opioid overdose
• Combination of opioids and alcohol is especially dangerous
• Cough suppression
• Opioids suppress the “cough center” in the brain

• Pupillary constriction
• pupillary constriction in the presence of analgesics is characteristic of opioid use
Pharmacological effects cont’d.
• Nausea and vomiting
• Stimulation of receptors in an area of the medulla called the chemoreceptor trigger zone
causes nausea and vomiting
• Unpleasant side effect, but not life threatening
• Gastrointestinal symptoms
• Opioids relieve diarrhea as a result of their direct actions on the intestines
• Other effects
• Opioids can release histamines causing itching or more severe allergic reactions including
bronchoconstriction
• Opioids can affect white blood cell function and immune function
Mechanism of action
• Activation of peripheral nociceptive fibers causes release of substance
P and other pain-signaling neurotransmitters from nerve terminals in
the dorsal horn of the spinal cord

• Release of pain-signaling neurotransmitters is regulated by

endogenous endorphins or by exogenous opioid agonists by acting
presynaptically to inhibit substance P release, causing analgesia
Adverse effects of opioids
Addiction: compulsive substance use despite harm =
DSM-IV dependence, at least 3 of the following:

 Tolerance
 Withdrawal
 Greater amounts/longer period than intended
 Persistent desire/unsuccessful efforts to cut down
 Inordinate amount of time obtaining, using, or recovering
 Important social, occupational or recreational activities given up or reduced due to substance use
 Use continued despite knowledge of having a persistent or recurrent physical or psychological problem
likely caused or exacerbated by substance

Incidence in opioid treatment for pain: ~2% per year

Contrast with: “Physiologic Dependence”
Adverse effects, continued
• Misuse  Use other than how prescribed:
• To get high
• More than prescribed
• Selling, trading = “diversion”
 Opioid Receptors
• Opioid receptors—binding sites not only for endogenous opiates but
also for opioid analgesics to relieve pain. Several types of receptors:
Mu, Kappa, Delta, Epsilon and Sigma.
Receptor Theories
Multiple Analgesic Receptors

* Three different analgesic receptors (mu, kappa and delta)

* Binding sites for all three receptors contain ionic, hydrogen bonding and
hydrophobic regions as proposed by Beckett-Casy

* Activation of all three produce analgesia, but differ in other effects

* All three interact with morphine

* Potential to target drugs selectively

Mu Receptor (m)

* Morphine binds strongly

* Activation produces analgesia plus side effects

(respiratory depression, euphoria, addiction)

* G-Protein coupled receptor

* m-Receptor subtypes identified which may allow separation of analgesia from

side effects

* m-Receptors related to all sources of pain stimuli

Kappa Receptor (k)

* Morphine binds less strongly

* Activation produces analgesia plus sedation

* Insignificant side effects

* Potential target for safe analgesics (compounds acting as agonists at k,

antagonists at m and no activity at the d receptor).

* G-Protein-coupled receptor

* k Receptors related to non-thermal pain induced stimuli

Delta Receptor
• It is unclear what delta’s responsible for.
• Delta agonists show poor analgesia and little addictive potential
• May regulate mu receptor activity
Mu-Receptor: Two Types
• Mu-1
• Located outside spinal cord
• Responsible for central
interpretation of pain
• Mu-2
• Located throughout CNS
• Responsible for respiratory
depression, spinal analgesia,
physical dependence, and
euphoria
Kappa Receptor

• Only modest analgesia

• Little or no respiratory depression
• Little or no dependence
• Dysphoric effects
Delta Receptor (d)

* Morphine binds strongly

* Receptor for enkephalins

* Activation produces analgesia plus some side effects

* G-Protein-linked receptor

* d receptors related to pain induced stimuli from all sources

Sigma Receptor (s)

* Activated by some opoid analgesics (e.g. nalorphine)

* Non-analgesic, non-opoid receptor

* Activation produces hallucinogenic effects

* Thought to be responsible for effects of phencyclidine (PCP) (Angel Dust)

Main effects of opioids at opioid receptors

Blue = Agonist (Blue) = Partial agonist Red = Antagonist

Mu and Kappa Receptor Activation

Response Mu-1 Mu-2 Kappa

Analgesia

Respiratory
Depression
Euphoria

Dysphoria

Decrease GI
motility
Physical
Dependence
Opiates
Natural Semi-
alkaloids synthetics

morphine heroin

oxycodone
codeine

hydrocodone

thebaine buprenorphine
naloxone
© AMSP 29
 Terminology

• Pure Agonist: has affinity for binding plus efficacy

• Pure Antagonist: has affinity for binding but no efficacy; blocks action of
endogenous and exogenous ligands

• Mixed Agonist-Antagonist: produces an agonist effect at one receptor and an

antagonist effect at another

• Partial Agonist: has affinity for binding but low efficacy

Opioids
Pure Mixed
Antagonists others
agonists agonists/
PURE antagonists
naloxone
FULL
tramadol
• morphine
• oxycodone naltrexone
• fentanyl
buprenorphine
PARTIAL
butorphanol
nalbuphine
pentazocine
© AMSP 31
Binding Sites

© AMSP 32
Pharmacokinetics
OPIOID MORPHINE METHADONE

Plasma ½ life ~3 hr 24 hr
Duration - ~5 hr ~6 hr
analgesia
Stored in body Limited Significant
IM/oral 6/1 2/1
potency
Elimination Kidney>>Gut Kidney=Gut
© AMSP 33
© AMSP 33
Chronic Pain
• Pain lasting most of the day during most days for > 3
months
• Point prevalence in U.S. adults: 15-20%
• Lifetime prevalence in U.S. adults: 50-75%
• Pain is most often-reported symptom in office visits after
URI
• Multi-faceted disorder that, by definition,
has bio- psycho- social components
 Types of Pain
Nociceptive pain -

mechanical, thermal, chemical activation of nociceptors

somatic pain: response to tissue injury
inflammatory mediators: prostaglandins, substance P,
bradykinin

Neuropathic pain -

damage to nerves (trigeminal neuralgia, postherpetic

pain, diabetic neuropathy)
 Pain Assessment
Two things must be determined before treating
pain.
1. Type of pain ( quality of pain)
 Somatic pain
 Visceral pain
 Neurophatic pain
In most cancers pain, mostly combined form
2. Intensity of pain (quantity of pain)
 Mild pain 1–3
 Moderate pain 4–7
 Severe pain 8 – 10
Three-Step ladder of WHO
Step III
Severe pain,
Seveare pain Strong Opioid analgesics
Step II Moderate Pain ± Non-opioid analgesics
For mild to moderate pain, ± adjuvant analgesics
Pain level

Mild Opioid analgesics

± Non-opioid analgesics
± adjuvant analgesics
Step I Mild Pain
Non-opioid analgesics
± adjuvant analgesics
Pain
Strong opioids
Morphine (MST Continus)
Pain
Mild Opioid
Codeine or Tramadol
Paracetamol+Codeine
paracetamol+Tramadol
APAP/NSAIDs ± adjuvants
APAP /NSAIDs ± adjuvants
Successive change
Algorithm for Opioid Treatment of Chronic
Pain
Patient Selection

Initial Patient Assessment

Alternatives
Comprehensive Pain Management Plan to Opioid
Therapy

Trial of Opioid Therapy

Patient Reassessment

Continue Opioid Therapy Implement Exit Strategy

2
Questions to Consider Before Initiating
a Trial of Opioid Therapy
• What pain syndromes are appropriate for opioid analgesia?
• What patients are appropriate candidates for opioid analgesia?
• Should opioids be the first analgesic class prescribed?
• What patients are at high risk for abuse and diversion
of opioids?

13
 Narcotic Analgesics
• Relieve moderate to severe pain by inhibiting release of Substance P
in central and peripheral nerves; reducing the perception of pain
sensation in brain, producing sedation and decreasing emotional
upsets associated with pain
 Narcotic Analgesics
• Can be given orally, IM, sub q, IV or even transdermally
• Orally are metabolized by liver, excreted by kidney—caution if
compromised
• Morphine and meperidine produce metabolites
• Widespread effects: CNS, Resp., GI
 What is MST?
MST is Morphine Sulfat Tablet Continues release
Onset 3 hours an duration 12 hours.
Tablet 10 mg, 15,30mg
Establish total dose of morphine needed in 24
hour , than divide into 2 for every 12 hours.
 Agonists/Antagonists
Have lower abuse potential than pure agonists
• Buprenex (buprenorphine)
• Nubain (nalbuphine)
• Talwin (pentazocine)
• Stadol (butohanol)—also in nasal spray
 Individual Drugs
• Agonists have activity on mu and kappa opioid receptors
• Agonist/antagonists have agonist activity in some receptors;
antagonists in others. Have lower abuse potential than pure agonists;
because of antagonism—can produce withdrawal symptoms
• Antagonists are antidote drugs
 Contraindications to Use
• Respiratory depression
• Chronic lung disease
• Chronic liver or kidney disease
• BPH
• Increased intracranial pressure
• Hypersensitivity reactions
Opioid withdrawal - abstinence syndrome

Severity depends on dose used and rate of elimination.

Rhinorrhea
Lacrimation
Chills
Goose flesh - ‘cold turkey’
Muscle aches
Diarrhea
Yawning
Anxiety
Hostility

Hyperalgesia

Precipitated withdrawal by a partial agonist or antagonist administration

 Withdrawal

R
Clonidine, an 2-adrenergic receptor R
agonist, is effective at reducing the
sympathetic nervous system
hyperactivity associated with acute
opiate withdrawal.
Opiate gone
R mOR
Hyper-Excitability
state

Excitatory drive

Noradrenergic neuron in the locus ceruleus

What is drug addiction? Correct use of prescribed medications for pain, anxiety
and hypertension produce tolerance and physical dependence.

Addiction is:
compulsive drug use,
obsessive thoughts about drug,
use despite objective evidence of harm,
loss of control of drug use,
high risk of relapse once abstinent.

Commonly Abused Prescription Opiates

Buprenorphine (Buprenex, Subutex, Suboxone)
Codeine
Fentanyl (Actiq, Sublimaze, Duragesic)
Hydrocodone (Vicodin, Vicoprofen)
Hydromorphone (Dilaudid)
Meperidine (Demerol)
Methadone (Methadose, Dolophine)
Morphine (MS Contin, Avinza, Oramorph SR)
Oxycodone (OxyContin, Percocet, Percodan)
Propoxyphene (Darvon)
“Molecular Basis of Addiction”

• Voluntary intake
tolerance readily reversible
physical dependence
sensitization

• Involuntary - compulsive intake

cravings, obsession, self-destructive behavior
Addiction - high relapse risk
Progression to Addiction

challenges at the molecular front:

identify molecular and cellular changes in the addicted brain

genes controlling risk of addiction
molecular events controlling relapse risk
History and Background
• Invention of the hypodermic needle in 1856 produced drug abusers
who self administered opioids by injection
• Controlling the widespread use of opioids has been unsuccessful
because of the euphoria, tolerance and physiological dependence
that opioids produce
Initiating Opioid Therapy
You’ve made the decision to prescribe opioid analgesics
for your patient. Now you must:
• Consider cost, tolerability, ease of administration, compliance
• Decide whether to start a short-acting opioid analgesic or a low dose
of a long-acting opioid analgesic, with or without short-acting
“rescue” doses if breakthrough pain occurs
• Develop and document an Exit Strategy

14
Create an Exit Strategy
• Upon initiating opioid therapy, agree with patient on criteria for
failure of the trial
• Common failure criteria include:
• lack of significant pain reduction
• lack of improvement in function
• persistent side effects
• persistent noncompliance
• Document method for tapering off opioids if trial is not successful

15
 Addiction
Abuse/Dependence

Prescription Drug Misuse

Aberrant Medication-Taking Behaviors

(AMTBs)
A spectrum of patient behaviors
that may reflect misuse

Total Chronic Pain Population

Adapted from Steve Passik. APS Resident Course, 2007

Which prescription medications are most
likely to be abused?
Commonly Abused Medications

• Opioids
• CNS Depressants
• Benzodiazepines
• Barbiturates
• Stimulants
• Others
When Are Opioids Indicated?
• Pain is moderate to severe
• Pain has significant impact on function
• Pain has significant impact on quality of life
• Non-opioid pharmacotherapy has been tried and
failed
• Patient agreeable to have opioid use closely
monitored (e.g. pill counts, urine screens)
Opioid Efficacy in Chronic Pain
• Most literature surveys & uncontrolled case series
• RCTs are short duration <4 months with small sample
sizes <300 pts
• Mostly pharmaceutical company sponsored
• Pain relief modest
• Some statistically significant, others trend towards benefit
• One meta-analysis decrease of 14 points on 100 point scale
• Limited or no functional improvement

Balantyne JC, Mao J. NEJM 2003

Martell BA et al. Ann Intern Med 2007; Eisenberg E et al. JAMA. 2005
90% of Cancer Pain can be managed by
using WHO Step Ladder.

WHO Step Ladder

Severe Pain

Moderate Pain
Strong Opioid
Mild Pain ± nonopioid
Mild Opioid ± adjuvant
Nonopioid ± nonopioid
± adjuvant  Morphine
± adjuvant - Rapid relies; tab
 Codein or Tramadol or liquid
 Acetaminophen ± Paracetamol - Slow relies MST
 Ibuprofen or
 Fentanyl Patch
 Celecoxibe ± NSAID or Coxib

Modify AHT
 Stopping Opioid Analgesics

• Patient is not improving and may have opioid-resistant

pain
• Some patients experience improvement in function and
pain control when chronic opioids are stopped
• Patient may have a new problem – “opioid dependence
(addiction)” and may need substance abuse treatment
• Be clear that you will continue to work on pain
management using non-opioid therapy
• Taper patient slowly to prevent opioid withdrawal
• The use of opioid analgesic therapy requires careful
assessment and tailored monitoring approaches
• Diagnosing addiction during pain management is
difficult and requires careful monitoring
• Usual substance abuse risk factors probably apply to
prescription opioid abuse
• Manage lack of benefit by tapering opioids
• Manage addiction by tapering opioids and referring to
substance abuse treatment
Employ Rational Polypharmacy
• Anti-nociceptive agents
• NSAIDs
• Acetaminophen
• Opioids
• Anti-neuropathic agents
• Anti-convulsants
• Tricyclics
• Anti-depressants
Informed consent
• Communication of risks, potential benefits,
goals/expectations, and treatment and monitoring
plans
• Written agreements or ‘contracts’
• Educate patient about safe opioid use
• Clearly define acceptable behavior
Dependence
• 3+ in same 12 months
• Tolerance
• Withdrawal
• Larger & longer use than intended
• Can’t quit
• Much time obtaining, using, or recovering
• ↓ activities
• Continued use despite problems

© AMSP 67
Abuse
• Not if dependent
• 1 in 12 months:
• Failure to fulfill role
• Use in hazardous situations
• Legal problems
• Use despite problems

© AMSP 68
Opioid Tolerance
• With repeated use
• Need ↑ doses to maintain effect
• Can see in pain patients
• Adaptation of receptors
• Different rates for each effect

© AMSP 69
 Opioid Withdrawal
• After quit or ↓chronic use or antagonist
• Opposite to agonist effects
• DSM-IV criteria: 3+ (minutes to days):
• Unhappy mood
• Muscle aches
• Tearing/runny nose
• Pupillary dilation
• Goose bumps or sweating
• Nausea/Vomiting
• Diarrhea – Fever - Yawning

© AMSP 70
Opioid Overdose
• Recent use
• Life threatening
• Constricted pupils
• 1+:
• Drowsiness or coma
• Slurred speech
• Poor attention and memory

© AMSP 71
 Pharmacological Treatment

1. Methadone
 Full µ agonists
 Once/day dosed
 40-60 mg/d: sufficient to block withdrawal sx.
2. Buprenorphine/Naloxone
 µ Receptor partial agonist
 Kappa receptor partial antagonist
 12-16 mg/d
 Combination ↓ risk of diversion

© AMSP 72
Psychosocial Treatment
• Specialized programs
• Cognitive behavioral therapy
• Behavioral therapy
• Psychodynamic/interpersonal
• Recovery-oriented therapies
• Group and Family therapy
• Self-help groups: NA, Al-Anon

© AMSP 73
 Stopping Opioid Analgesics

• Patient is not improving and may have opioid-resistant

pain
• Some patients experience improvement in function and
pain control when chronic opioids are stopped
• Patient may have a new problem – “opioid dependence
(addiction)” and may need substance abuse treatment
• Be clear that you will continue to work on pain
management using non-opioid therapy
• Taper patient slowly to prevent opioid withdrawal
 Antagonists
• Revex (nalmefene)—longer duration of action than Narcan
• Narcan (naloxone)
• ReVia (naltrexone)-used in maintenance of opiate-free states in opiate
addicts
 Management of Withdrawal Symptoms

• Methadone
• Clonidine (norepinephrine)
• Gradually decrease dosing so not to cause withdrawal s/s
Employ multi-modal approach

Behavioral
SELF CARE therapies
SELF EFFICACY

Pharmacologic
treatment Physical activity
TAPERING FLOWCHART
• START HERE

• Consider opioid taper for patients with opioid MED > 120/methadone > 40, aberrant
behaviors, significant behavioral/physical risks, lack of improvement in pain and function.
• Consider benzodiazepine taper for patients with aberrant behaviors, behavioral risk
factors, impairment, or concurrent opioid use.
• 1 Explain to the patient the reason for the taper: “I am concerned…”
• 2 Determine rate of taper based on degree of risk.
• 3 If multiple drugs involved, taper one at a time (e.g., start with benzos, follow with
opioids).
• 4 Set a date to begin, provide information to the patient, and set up behavioral supports,
prior to instituting the taper. See page 26 of OPG guidelines.
OPIOID TAPER

• Opioids (not methadone)

• Basic principle: For longer acting drugs and a more stable patient, use slower taper. For shorter acting drugs,
less stable patient, use faster taper.
• 1 Utilize the drug the patient is taking as the tapering medication. If you switch medications, follow MED
equivalency chart and then reduce the dose by 25–50% as starting dose. Metabolic variability can be quite
significant. Utilize a 90% dose reduction if switching to methadone. See dose calculator link below.
• 2 Decrease total daily starting dose by 5–15% per week in divided doses.
• 3 See patient frequently during process and stress behavioral supports. Consider UDS, pill counts, and PDMP
to help determine adherence.
• 4 After ¼ to ½ of the dose has been reached, with cooperative patient, you can slow the process down.
• 5 Consider adjuvant medications: antidepressants, NSAIDs, clonidine, anti-nausea, anti-diarrhea agents.
MED Morphine equivalent dosing
• morphine (reference) 30 mg
• Codeine 200 mg
• Fentanyl transdermal 12,5 mcg/hr
• Hydrocodone 30 mg
• Hydromorphone 7,5 mg
• Methadone : chronic: 4 mg
• Oxycodone 20 mg
• Oxymorphone 10 mg
• TAPERING FLOWCHART

• BENZODIAZEPINE TAPER
• Basic principle: Expect anxiety, insomnia, and resistance. Patient education and support very important. Risk
of seizures with abrupt withdrawal increases with higher doses. The slower the taper, the better tolerated.

• 1 Slow taper: Calculate total daily dose. Switch from short acting agent (alprazolam, lorazepam) to longer
acting agent (diazepam, clonazepam). Upon initiation of taper reduce the calculated dose by 25–50% to
adjust for possible metabolic variance.
• 2 First follow up visit 2–4 days after initiating taper to determine need to adjust initial calculated dose.
• 3 Reduce the total daily dose by 5–10% per week in divided doses.
• 4 After ¼ to ½ of the dose has been reached, with cooperative patient, you can slow the taper.
• 5 Consider adjunctive agents to help with symptoms: trazodone, buspirone, hydroxyzine, clonidine,
antidepressants, neuroleptics, and alpha blocking agents.
• 1 Rapid taper: See the tapering guidelines on page 28 of the OPG guidance documents.
Factors and activities that can help avoid
accidental opioid overuse
• Screen patients for respiratory depression risk factors
• Assess the patients previous history of analgesic use or abuse,
duration and possible side effects to identify potential opioid
tolerance or intolerance
• Skin assessment to rule out the possibility that patients has an applies
fentanyl patch
• Use individualized multimodal treatment plan to manage pain
• Extra precautions with patients who are new to opioids or who are
being restarted on opioids
Factors and activities that can help avoid
accidental opioid overuse (cont)
• Consult a pharmacist or pain management expert when converting
from one opioid to another, or changing the route of administration
• Avoid rapid dose escalation of opioid analgesia above routine dose
levels in opioid-tolerant patients
• Take extra precautions when transferring patients between care units
and facilities, and when discharging patients to their home
• Dosing should be based on the individual patient’s need and
condition
Summary
• The use of opioid analgesic therapy requires careful
assessment and tailored monitoring approaches
• Diagnosing addiction during pain management is
difficult and requires careful monitoring
• Usual substance abuse risk factors probably apply to
prescription opioid abuse
• Manage lack of benefit by tapering opioids
• Manage addiction by tapering opioids and referring to
substance abuse treatment
MATUR NUWUN