Opioids, their use, addiction, management

2. Current Status of Opioids In
Therapeutics

3. Opioids
• Opium
• Opiate
• Opioid

4. Fear of Addiction
Undertreatment
Vague therapeutic use

5. Receptors
• μ
• κ
• δ
• Nociceptin Opioid Receptor
• ε
• σ

6. Receptor Location Endogenous
Ligand
Agonist Effect
μ SSC, PAG, Thalamus,
Hypothalamus, NTS,
PVG, Medulla, SG
cells, myentric plexus
β-endorphin
Endomorphin
Morphine
Supraspinal
analgesia, Resp.
Depression,
Vomitting
κ Neurohypophysis,
Hypothalamus, Spinal
cord
Dynorphins
Ketocyclazocine
Nalorphine
Sedation,
Dysphoria,
Minimal abuse
potential
δ Similar to μ receptor,
Vas deferens
Enkephalins Similar to μ
Nociceptin
Opioid
Receptor
Hippocampus, Cortex,
Sensory neurons,
Spinal Cord
Nociceptin
?
(Hyperalgesia)
ε Neuroendocrinal areas β-endorphin
σ ? ? N-allyl
normetazocine
?
(Anti-tussive)

7. Parameter Endorphin Dynorphin Enkephalin Nociceptin
Analgesia
Supraspinal
Spinal
Peripheral
+++ (μ1)
++ (μ2)
++
+ (κ3)
+ (κ1)
++
-
++
-
+/−
+/−
+/−
Resp.
Depression +++ (μ2) ± ++ -
Euphoria +++ (μ1) - - -
Reward ++ - ++ ++
Dysphoria - +++ - -
Miosis ++ + - -
Constipation ++ (μ2) + + -
Sedation ++ ++ - -
Dependence +++ (μ1) + - -

8. Classification
• Opium Alkaloids:
• Phenanthrenes – Morphine and congeners
• Benzyl isoquinolones – Papaverine and congeners

9. Classification
1. Naturally occuring: Morphine, Codeine
2. Semi-synthetic: Diamorphine, Hydrocodone
3. Synthetic:
a. Phenyl Piperidines: Meperidine, Fentanyl
b. Morphinan: Butorphanol, Levorphanol
c. Benzomorphans: Pentazocine, Phenazocine
d. Diphenyl Compounds: Methadone
e. N-allyl compounds: Nalorphine, Naloxone

10. Classification
Pure Antagonists
• Naloxone
• Nalmexone
• Nalbuphine
• Naltrexone
Partial Agonists
• Thebaine derivative
Buprenorphine
Pure Agonists
• Morphine
• Codeine
• Fentanyl
• Pethidine
• Methadone
Agonist-
Antagonist
• Butorphanol
• Levorphanol
• Pentazocine
Partial Antagonist
• Nalorphine

11. Mechanism of Action
• No direct link with effector proteins
• Message is relayed via a G-protein
• Couple to inhibitory G-proteins
i. closing of voltage sensitive calcium channels (VSCC);
ii. stimulation of potassium efflux leading to
hyperpolarization; and
iii. inhibition of adenylyl cyclase leading to reduction in
cAMP.

16. Therapeutic Uses
• Analgesia
• Acute Left Ventricular Failure
• Neurolept Analgesia
• Anti-tussive
• Anti-Diarrheal
• De-addiction

17. Pain
• “an unpleasant sensory or emotional experience
associated with actual or potential tissue damage”
- Merskey (1986)
• Nociception
• Transduction
• Transmission
• Modulation
• Perception

20. Classification
• Origin
• Pathology
• Onset and Duration

21. Origin
• Somato-sensory Pain
• Deep Visceral Pain
• Referred Pain
• Psychogenic Pain
Classification of Pain

22. Pathology
• Nociceptive pain
• Neuropathic Pain
Classification of Pain

23. Onset and Duration
• Acute-
• Surgical-
• Pre-operative
• Intra-operative
• Post-operative
• Non-surgical-
• Traumatic
• Organic- Physiological / Pathological
• Psychosomatic
Classification of Pain

24. • Chronic-
•Oncogenic
•Non-oncogenic
• Organic
• Neuropathic

25. Somatosensory Deep Visceral Referred Psychogenic
Morphine +++ + + ++
Oxycodone +++ ++ + +
Hydromorphone +++ ++ - +
Fentanyl +++ + ++ ++
Buperonorphine ++ +++ - -
Pentazocine +++ + ++ ++
Butorphanol + +++ - ++
Methadone + +++ - ++

26. Acute Pain
• Surgical:
• Preoperative:
Pentazocine (30-60mg/ml), Pethidine (50-100mg/ml)
• Intraoperative:
• Fentanyl – Induction, adjuvant (2-20 mcg/kg, 50-100)
• Remifentanil
• Morphine – Analgesic (0.3 – 0.6 mg/kg)
• Pethidine – Analgesic
• Butorphanol – Analgesic (0.06 – 12.5 mg/kg)
• Buprenorphine – Adjuvant (0.3 – 0.6 mg)

27. Acute Pain
• Post-operative:
• Monitored Care: Fentanyl
• Unmonitored Care: Pethidine, Pentazocine, Butorphanol,
Morphine, Buprenorphine
• Shivering: Pethidine
• Labor Analgesia: Pethidine, Fentanyl, Diamorphine,
Pentazocine

28. Acute Pain
• Non-Surgical:
• Traumatic:
• MI – Morphine, Fentanyl
• Road traffic accidents – Pethidine, Fentanyl,
Morphine, Pentazocine
• Battlefield /Post-traumatic – Buprenorphine/Naloxone,
Pethidine, Morphine
• Dysmenorrhea – Pethidine, Dextromethorphan

29. Acute Pain
• Organic:
• Physiological: Pethidine, Fentanyl
• Pathological: Dihydrocodeine, Codeine, Morphine
• Psychosomatic:
• Hydrocodone, Pethidine, Oxycodone,
Hydromorphone

30. Chronic Pain

31. Chronic Pain
• Oncogenic:
• Morphine
• Oxycodone
• Diamorphine
• Hydromorphone
• Fentanyl
• Butorphanol
• Diamorphine
• Meperdine

32. Chronic Pain
• Non-oncogenic:
• “Chronic Non-Malignant Pain” (CNMP)
• Pregabalin, Gabapentin
• After all other therapies fail
• Route – simple (for long term administration)
• Monitor pain, titrate doses
• Taper once bearable to minimum dose
• Breakthrough Pain: Morphine, Oxycodone
Fentanyl

33. Acute LVF
• Morphine: Venodilator, relieves dyspnea
• Reduces cardiac filling pressures
• Preload reduction
• Pulmonary congestion reduced
• Reduces sympathetic drive
• Morphine, Codeine, Hydromorphone

34. Pulmonary Hemorrhage
• Relieve dyspnea
• Anxiolytic

35. Neurolept Analgesia
• Semiconscious non-reactive state
• Fentanyl (0.5-1 mg)+ Droperidol (2.5-5 mg) (+ N2O)
• Sedation, tranquility, immobility, and antiemesis
• Ophthalmic operations, endoscopic and
bronchoscopic examinations, neurodiagnostic
procedures, and excision of epileptogenic foci.

36. Anti-tussive
• Evidence shows that antitussive action is due to
• μ2 receptor action
• δ antagonism
• Actions via increase in 5HT levels
• Chronic Resistant Cough may be due to release of
neurokinins from NTS and Aδ and C fibres
• Codeine (15-20 mg), Dextromethorphan (10-30 mg)

37. Anti-diarrheal
• Induce a sustained segmental contraction of intestinal
smooth muscle, which prevents the rhythmic waves
of contraction and relaxation of smooth muscle that
occur with normal peristalsis
• Loperamide (2-4 mg), Diphenoxylate (2.5 mg), Codeine

38. Addiction
• American Society of Addiction Medicine (2011)
• “A primary, chronic disease of brain reward, motivation, memory
and related circuitry.
• Dysfunction in these circuits leads to characteristic biological,
psychological, social and spiritual manifestations.
• This is reflected in an individual pathologically pursuing reward
and/or relief by substance use and other behaviors.
• Addiction is characterized by inability to consistently abstain,
impairment in behavioral control, craving, diminished recognition of
significant problems with one’s behaviors and interpersonal
relationships, and a dysfunctional emotional response.
• Like other chronic diseases, addiction often involves cycles of
relapse and remission. Without treatment or engagement in recovery
activities, addiction is progressive and can result in disability or
premature death”

39. Addiction
• Substance dependence is a pattern of
maladaptive behaviours, including loss of
control over use, craving and preoccupation
with non-therapeutic use, and continued use
despite harm resulting from use (with or
without physical dependence or tolerance)
[WHO, DSM].

40. Dependence vs. Addiction
• Physical dependence occurs because of normal
adaptations to chronic exposure to a drug.
• Addiction, which can include physical dependence, is
distinguished by compulsive drug seeking and use
despite sometimes devastating consequences
• Dependence is often accompanied by tolerance, or the
need to take higher doses of a medication to get the
same effect.

41. Opioids: Drugs of Abuse
• Most commonly abused drugs
• Euphoriant, reward behaviour, antidepressive,
anxiolytic and antipsychotic effects
• Self medication, chronic use, peer pressure
• Intensify their experience by taking the drug in ways
other than those prescribed
• Oxycodone

42. Tolerance
• State of physiologic adaptation in which exposure to
a drug induces changes that result in diminution of
one or more of the drug’s effects over time
• Decreased effect from a constant dose of drug or by
an increase in the minimum drug dose required to
produce a given level of effect
• Changes in the binding of a drug to receptors or
changes in receptor transductional processes related
to the drug of action

43. Tolerance
• Internalization of mu and delta opioid receptors
• Downregulation of second messengers G-proteins
and adenylyl cyclase/cAMP
• Once the exogenous opioids are removed from the
system, the remaining endogenous opioids are unable
to sufficiently activate the small number of remaining
receptors (withdrawal).

44. Withdrawal Reactions
Acute Action
• Analgesia
• Respiratory Depression
• Euphoria
• Relaxation and sleep
• Tranquilization
• Decreased blood pressure
• Constipation
• Pupillary constriction
• Hypothermia
• Drying of secretions
• Reduced sex drive
• Flushed and warm skin
Withdrawl Sign
• Pain and irritability
• Hyperventilation
• Dysphoria and depression
• Restlessness and insomnia
• Fearfulness and hostility
• Increased blood pressure
• Diarrhea
• Pupillary dilation
• Hyperthermia
• Lacrimation, runny nose
• Spontaneous ejaculation
• Chilliness and “gooseflesh”

45. Toxicity
• CNS depression
• Pinpoint pupils
• Respiratory Depression
• Decreased Heart rate
• Cyanosis
• Seizures and muscle spasms
• Drowsiness
• Conjunctival injection
• Ventricular arrhythmias
• Hypertension and pupillary dilation may present because of
CNS hypoxia
• Pruritus, flushed skin and urticaria

46. De-addiction
• Detoxification
• Relapse Prevention
• Maintenance Treatment Programs

47. Detoxification
• Supervised withdrawal from opioids
• Minimise or suppress opioid withdrawal symptoms
• tapered doses of Methadone or Buprenorphine
• masking withdrawal symptoms using a2-adrenergic
agonists, such as Clonidine or Lofexidine
• by using opioid antagonists such as Naltrexone, usually in
combination with other drugs (e.g. a2-adrenergic agonists,
benzodiazepines, and buprenorphine)
• Ultra Rapid Opioid Detoxification (UROD)

48. Relapse Prevention
• Poor retention in psychosocial abstinence-oriented
treatment programs
• Use of Opioid Antagonist – Naltrexone
• Produce no opioid-effects
• Solely block the effects of opioid agonists by occupying
opioid receptor sites in the brain
• Crucial in first few months after detoxification

49. Maintenance Treatment
• Antagonist:
• Oral Naltrexone (50mg)
• Competitive blockade
• Poor patient compliance
• Blocks physical dependence, not cravings
• Injections and Depot preperations
• Severe cases (under legal observation)

50. Maintenance Treatment
• Agonist:
• Methadone or Buprenorphine
• Opioid dependence is a chronic, relapsing disorder,
and that for some patients, abstinence from all
opioids is an unrealistic goal in the short- to
medium-term
• Methadone (15-40mg) – cross tolerance
• Buprenorphine (4-24mg)– competitive blockade

51. Other Uses
• Methadone – Leukemia
• Induces cell death
• Buprenorphine – Refractory Depression
Neonatal Abstinence Syndrome
• Nalorphine – With Morphine
Check ex-addicts for relapse
• Naloxone – Depersonalization Disorder
With Buprenorphine in labor analgesia

52. Other Uses
• Naltrexone:
• Alcohol dependence
• ? Depersonalization disorder
• Self-injurious behaviour
• Behavioural Addiction
• Countering adverse effects of Interferon alpha
• Nalbuphine – Morphine induced pruritus

53. Other Drugs acting on Opioid Receptors
• Tramadol
• Clonidine, Dexmedomidine
• Ketamine
• Tapentadol
• Trimebutine

54. Drug Delivery Systems
• Oral:
Tablets
Liquids
Powders
Mucosal Gels
• Sustained release preperations: Morphine

55. Sublingual
• Fentanyl - Tablet: Abstral
Spray: Subsys
• Buprenorphine – Tablet: Subutex, Suboxone
Film: Suboxone

56. Buccal
• Fentanyl - Lozenges: Actiq
Tablet: Fentora
Soluble Film: Onsolis

57. Rectal
• Morphine
• Codeine
• Oxycodone
• Hydromorphone
• Buprenorphine

58. Subcutaneous
• Naltrexone Implants

59. Intramuscular
• Fentanyl
• Pethidine
• Pentazocine
• Naltrexone
• Buprenorphine
• Methadone
• Codeine
• Butorphanol
• Hydromorphone

60. Intravenous
• Fentanyl - Infusion
• Pethidine
• Morphine
• Methadone
• Buprenorphine
• Hydromorphone

61. Transdermal
• Fentanyl: Patch – Duragesic, DTrans
• Buprenorphine:

62. Intrathecal and Epidural
• Fentanyl
• Pethidine
• Morphine

63. Intranasal
• Fentanyl – Spray: Instanyl
Pectin Spray: Lazanda
• Butorphanol - Spray

64. Iontophoresis
• Fentanyl: PCTS – Ionsys
• Naltrexone
• Morphine

65. Recent
• ALKS 5461 – new opioid modulator
• Alkermes Company, Dublin Ireland
• Treatment of Depression
• Minimal Abuse potential

66. Recent
• Biomarker Hydrogel - nanoparticles
• ORL-1 agonists – heart failure, migraine
• Ro64-6198 – Anorexia, Antitussive
• JTC-801- analgesic, antidepressant
• J-113,397 – prevention of tolerance
• NKTR-181 – analgesia

67. Thank You!!