OPIOIDS : Principles of opioids and optimizing outcomes

Question 1

Pharmacokinetics

Answer 1

• What the body does to the drug
• ADME
  
  • Absorption
  • Distribution
  • Metabolism
  • Excretion

Question 2

Pharmacodynamics

Answer 2

What the drug does to the body

*

Question 3

Factors that affect pharmacokinetics of opioids

Answer 3

• Age
  
  • metabolism, volume of distribution, reduced in elderly
  • increased free concentrations in plasma
  • hepatic flow declined
  • increased CNS sensitivity
• Hepatic disease
  
  • Unpredictable
  • severe failure = marked sensitivity
  • reduction in plasma protein = increased plasma concentrations of drugs
• Renal failure
  
  • renally cleared metabolites accumulate
• Obesity
  
  • volume of distribution larger, longer half life, elimination
• Hypothermia, hyperthermia, hypotension, hypovolemia
  
  • variable absorption

Question 4

Pharmacokinetics : Absorption

Answer 4

• across lipid cell membrane
• passive process concentration gradient
• occurs in small bowel

Question 5

List causes of altered absorption

Answer 5

• delayed gastric emptying
• medications that delay emptying (opioids, ach)
• sustained release formulations need to stay in small bowel to be fully absorbed
  
  • may be reduced absorption if increased GI transit (maxeran, domperidone)

Question 6

Pharmacokinetics : Bioavailability

Answer 6

• percentage of drug that gains access unchanged to systemic circulation
• oral administration most relevant
• Extensive first pass metabolism in liver
  
  • low bioavailability of some drugs
• differences in bioavailability = challenges in safe dose selection between oral and parenteral

Question 7

List reasons that can alter bioavailability

Answer 7

• hepatic dysfunction
• exposure to drugs that induce or inhibit P450 system
• eg:
  
  • chronic liver disease, blood shunted from portal to venous system
  • bypasses hepatic enzymes and first pass effect
  • increased bioavailability of drug

Question 8

Pharmacokinetics : Distribution

Answer 8

• volume of distribution :
  
  • theoretical volume for total amount of drug needed to be uniformly distributed to achieve targeted blood concentration
• Volume for lipophilic drugs can be 4-5x body size

High volume of distribution

• drugs leaves plasma and goes intro extravascular components of body
• higher dose required to achieve blood concentration
• longer half life elimination

Low Volume of distribution

• more likely to stay in plasma
• lower dose required
• shorter half life

Question 9

List factors that affect the volume of distribution

Answer 9

• acid base disturbances
  
  • basic drugs tend to be more lipophilic
  • leave systemic circulation, higher volume distribition
  • acid drugs like albumin and bind to it, stay in plasma
• Lipophicility of drug
  
  • higher VD
  • Hydrophilic meds stay in plasma

Question 10

Diffusable fraction of opioids

Answer 10

• proportion of opioid that is unbound to plasma proteins
• capable of diffusing to site of action
• determines speed on onset of clinical effect
  
  • concentration of diffusable fraction
  • lipid solubility
  • diffuses across BBB

Question 11

Compare onset of action and reason for morphine and fentanyl

Answer 11

• Morphine:
  
  • high diffusable fraction, low lipid solubility
  • slow onset
• Fentanyl
  
  • high diffusable fraction, high lipid solubility
  • fast onset

Question 12

Pharmacokinetics : metabolism

Answer 12

• occurs in liver
• Phase I reactions :
  
  • oxidation, reduction, hydrolysis, isomerization
  • Oxidation catalyzed by CYP450 family of enzymes most important
• Phase II reacions:
  
  • conjugations, glucoronidation, methylation
• goal is to produce water soluble products that can be excreted by kidneys

Question 13

Pharmacokinetics : Elimination

Answer 13

• Liver
• Kidneys
• Clearance is volume of blood completely cleared of drug in unit of time
• determines half life and steady state

Question 14

Pharmacokinetics : define Half Life

Answer 14

• measure of time taken for half the drug in the body to be removed
• correlates closely with duration of action

Concerns:

• long half life accumulates for prolonged period of time
• concentration can surpass effective therapeutic range
• toxicity

Question 15

Pharmacokinetics : Steady State

Answer 15

• 5-6 half lives requried to reach steady state
• regardless of route of adminstration
• aim is to achieve intended effect without side effects
• swings between trough and peak:
  
  • amount depends on eliminimation half life and frequency of administration

Question 16

How much time does it take to reach steady state?

Answer 16

• depends on half life
• 5-6 half lives
• 95% of steady state drug concentration achieved with 4 half lives.
• relevant for first order kinetics (most drugs)
• Eg: half life of morphine is 2-4 hours.
  
  • given q4h
  • steady state 95% will be at 4x4 hours = 16 hours
  • can titrate every day then to ensure dose changes are at steady state

Question 17

Pharmacodynamics

Answer 17

• drugs produce effects by:
  
  • binding with receptors
  • modifyign enzyme processes
  • direct chemical or physical actions

Question 18

Opioid receptors

Answer 18

• Mu (MOR)
• kappa (KOR)
• delta (DOR)
• ORL-1 Orphan
  
  • opioid like receptor
  • (nociceptin peptide receptor NOR)
  • spinal cord
  • modulates stress response, movement, etc

Question 19

List endogenous opioids

Answer 19

• Encephalins
• Endorphins
• Dynorphins

Question 20

Mu Opioid receptor

Answer 20

• Gene OP3
• Expression
  
  • CNS (cortex, thalamus, hypothalamus, periaqueductal gray, amygdala)
  • Spinal cord
  • Peripheral nervous system
  • Immune cells
• Endogenous ligand
  
  • beta endorphin
  • encephalins
  • endomorphins
• Function
  
  • inhibits nociceptive pathways
  • all exogenous opioids can bind
  • analgesia
  • resp depression
  • reduce GI motility
  • mioisis
  • euphoria
  • sedation
  • dependence

Question 21

Kappa Opioid Receptor

Answer 21

• Gene OPRK1
• Expression:
  
  • CNS, same as Mu
  • no amygdala
  • spinal cord
  • PNS
• Endogenous ligand
  
  • Dynoprhins
• Function
  
  • modulation of pain
  • chemical and visceral and thermal pain
  • analgesia
  • responsible for lots of side effects
    
    • nausea and vomiting
    • dysphoria
  • mioisis
  • dysphoria
  • hallucinations
  • sedation

Question 22

Delta Opioid Receptor

Answer 22

• Gene OPRD1
• Expression
  
  • CNS (cortex, striatum, olfactory bulb)
  • PNS
• Endogenous ligand
  
  • encephalines
  • betaendorphins
• Function
  
  • analgesia
  • resp depression
  • reduced GI motility
  • tolerance
  • mood regulation

Question 23

Opioid AGONISTS

Answer 23

• binds to cell receptors to induce changes in cell that stimulate physiological activity
• no ceiling effect to analgesia
• log linear function of analgesia until either analgesia or adverse side effects occur
• most opioids are Full agonists
  
  • morphine,
  • HM,
  • oxycodone,
  • methadone,
  • fentanyl

Question 24

Partial AGONISTS

Answer 24

• low intrinsic efficacy
• lack of linear response in analgesia after dose escalation
• ceiling effect at less than maximum effect compared to full agonist
• Buprenorphine

Question 25

Potency

Answer 25

• dose response relationship
• intensity of effect of different drugs
• equianalgesic effects
• ratio of doses of 2 analgesics required to produce the same effect
• by convention, it is compared to 10 mg IV morphine

Question 26

Efficacy

Answer 26

• maximal reponse by active drug
• degree of analgesia after dose escalation through a range limited by adverse effects

Question 27

Opioid Mixed agonist / antagonists

Answer 27

• Agonist effects at one receptor
• Antagonist effects at another
• Eg. Nalbuphine
• Pentazocine
• when mixed antagonist-agonist is given with an agonist, the antagonist effect at mu receptor can cause withdrawal.

Question 28

Opioid ANTAGONISTS

Answer 28

• Interfere with action of agonist
• have no pharmacological action intrinsically
• competitive antagonists bind to same receptors as agonists
• non competitive antagonists block in other ways
• Eg Naloxone, Naltrexone

Question 29

List GI Side Effects of Opioids

Answer 29

• nausea
• constipation
• dry mouth
• vomiting
• Ileus

Question 30

List CNS side effects of opioids

Answer 30

• Somnolence
• COnfusion
• Myoclonus
• Nightmares
• hallucinations
• hyperalgesia

Question 31

List GU side effects of opioids

Answer 31

• Urinary retention

Question 32

List respiratory side effects of opioids

Answer 32

• decreased cough
• respiratory depression

Question 33

List skin side effects of opioids

Answer 33

• diaphoresis
• pruritis

Question 34

List Endocrine side effects of opioids

Answer 34

• Hypogonadism
• Immunosuppression

Question 35

Define Adverse drug effect

Answer 35

• unwanted or harmful reaction to drug
• when given under normal circumstances
• suspected to be related to drug

Question 36

Pharmacokinetic drug interactions

Answer 36

• changes in rate and extent of absorption
• rate of metabolism
• distribution
• renal exretion

Question 37

Common drug interactions

Answer 37

• GI tract
  
  • metoclopramide, ACh alter gastric emptying
  • alters speed of absorption
  • drugs that bind in GI tract (PPI, iron, cholestyramine) : decrease bioavailability
• Liver
  
  • changes in bioavailability
  • miss first pass metabolism
  • decreased clearance
• CYP450 interactions
  
  • inducers/inhibitors
• Kidney
  
  • loop diuretics compete for active tubular secretion
  • NSAIDS

Question 38

What happens if you give buprenorphine with Morphine?

Answer 38

• morphine induced analgesia reversed or limited by competetition of partial agonist buprenorphine.

Question 39

Immediate and Sustained Release

Answer 39

• IR:
  
  • absorbed in stomach and small bowel
  • complete in 1-2 hours of ingestion
• SR
  
  • smoother concentration profile in blood
  • extended duration and reduction in pill burden

Question 40

Transmucosal administration

Answer 40

• avoids first pass metabolism
• higher bioavailability
• faster onset of action

Question 41

Transdermal

Answer 41

• Lipid soluble drugs well absorbed through skin
• caution in cachexia and fever

Question 42

Opioid pharmacogenomics

Answer 42

• CYP2D6 allele
• genetic polymorphisms
• 4 phenotypes
  
  • poor metabolizers (10% caucasions, no analgesia)
  • intermediate
  • extensive
  • ultra metabolizers (3%, adverse effects, toxicity)
• CODEINE partially metabolized by CYP2D6
• Fatal neonatal opioid toxicity in children breastfed by mothers who are ultrarapid metabolizers

Question 43

Mixed mechanism Drugs

Answer 43

• Tramadol / Tapentadol
• centrally acting anaglesics
• Mu agonist AND monamine SE, NE reuptake inhibition
• ceiling dose

Question 44

WHO Analgesic ladder for Cancer Pain

Answer 44

Step 1 Mild Pain

• non opioid +/- adjuvant

Step 2 Moderate Pain

• Weak opioid +/- non-opioid +/- adjuvant

Step 3 Severe Pain

• Strong opioid +/_ non-opioid +/- adjuvant

Question 45

Why do some clincians prefer to omit the second step of the WHO ladder and move directly to step 3?

Answer 45

• Improved understanding of the metabolism of codeine
• Wider range of step 3 opioids available. Can use low dose of these
• Low dose strong opioid more efficient than switching mutiple times

Question 46

Codeine

Answer 46

• naturally occuring opium alkaloid
• low affinity for mu receptors, bioavailability 60-90%
• metabolized to morphine
  
  • codeine 6 glucoronide
  • M3G and M6G
• CYP 2D6 with ++ genetic polymorphism
• 1/2 life 2 hours, peak 1.5-2 h, duration 3-6h
• dose 30-60 mg po

Question 47

Oxycodone

Answer 47

• semi-synthetic congener of morphine
• high oral bioavailability 60-90%
• metabolized to oxymorphone in liver (not active)
• pure mu agonist
• more potent than morphine (1.5 :1)
• accumulates in renal failure
• CYP 3A4 and CYP 2D6

Question 48

Tramadol

Answer 48

• CYP 3A4 and 2D6
• Mu agonist
• Monoamine inhibitor (Serotonin and NE)
• Modest affinity for mu, weak affinity to delta and kappa
• can be reveresed by naloxone
• ceiling effect
• Side effects similar to morphine

Question 49

Tapentadol

Answer 49

• mu agonist
• NE reuptake inhibitor
• minimal 5HT inhibition
• no active metabolites, no drug drug interactions
• CI with MAOI
• limited evidence

Question 50

Morphine

Answer 50

• potent mu agonist
• liquid, IR, CR

Absorption

• Absorption is complete in upper small bowel

Metabolism

• pre systemic first pass metabolism in liver
  
  • bioavailability 20-30%
• t1/2 2-3 hours, duration 4-6 hours
• rectal bioavailability similar to oral
• M3G - no analgesic effects
  
  • does not bind to mu receptors
• M6G - active metabolite, binds to opioid receptors
  
  • potent analgesic
  • may cause toxicity

Excretion

• liver first pass
• Kidney excretes metabolites

Other

• Hydrophilic
  
  • epidural this means no systemic absorption, long 1/2 life in spinal fluid. extensive rostral redistribution

Question 51

Morphine potency and conversions

Answer 51

• 1:3 or 1:2 IV: oral
• Single dose vs chronic dosing
• M6G accumulation may be greater with oral than parenteral administration

Question 52

Sustained release morphine

Answer 52

• peak of 3-6 hours
• duration 12-14 hours
• do not use for titration period

Question 53

Methadone

Answer 53

• Synthetic opioid at mu receptor NMDA receptor antagonist
• oral : parenteral potency 1:2
• single doses, potency similar to morphine
• repeated doses = increased potency
• half life 12-150 hours with variability
• Steady state 1 week
• Ratios:
  
  • 4:1 MEDD < 90
  • 8:1 MEDD 90-300 mg
  • 12:1 MEDD >300 mg

Question 54

Meperidine

Answer 54

• synthetic opioid
• mu agonist
• active metabolite is norpethidine:
  
  • twice as potent as a convulsant
  • half as potent as analgesic
  • accumulates ++ with repeated dosing
• CNS excitability, mood , tremor, myoclonus, seizure
• naloxone not effective for seizures, may even preciptate seizure by blocking anti seizure action of meperidine
• Accumulation in renal function
• 5HT4 syndrome with MAOI combination
• NOT USEFUL IN CANCER PAIN

Question 55

Hydromorphone

Answer 55

• semi synthetic morphine congener
• 5x as potent at morphine
• potency ratio:
  
  • equianalgesic ratio for parenteral HM : M differs
    
    • 7:1 when going morphine to HM
    • 4:1-8:1 when going HM to morphine
  • Oral equianalgesic ratio
    
    • 7.5-1
  • IV hm : oral HM 1:2
• mu agonist
• high concentrations available for sc infusion
• Metabolism:
  
  • oral bioavailability 60-80%
  • partially metabolized in liver
  • H3G metabolite
  • largely excreted unchanged in liver

Question 56

Fentanyl

Answer 56

• semi synthetic opioid
• highly selective mu agonist
• 100X as potent as parenteral morphine
• ++ lipophilic
• rapid onset 3-5 minutes
• duration 30-60 minutes
• t 1/2 3-12 hours (longer with repeated administration –> fat sequestration)
• NO active metabolites
• some evidence less constipating

Question 57

Transdermal fentanyl

Answer 57

• TD absorption bc low molecular weight and high lipid solubility of fentanyl
• serum {} increases gradually, levels of at 12-24 hours
• after removal, serum [] falls to 50% at 17 hours
• avoid in patients with unstable pain
• subcutaneous depot of drug that maintains plasma concentration

Rotating to patch

• takes 8-12 hours to get analgesia
• need to continue IR original opioid until then

Patch placement

• minimal skin movement
• cachexia may not absorb
• no heat pads
• watch for fever
• cold = less absorption

Question 58

When you might choose a fentanyl patch

Answer 58

• loss of oral route (head and neck ca, obstruction)
• poor compliance with po meds
• opioid toxicity or intolerance of other opioids
• stable opioid dosing
• patient preference

Avoid if unstable pain

++ Education when starting

Question 59

Oral Transmucosal fentanyl

Answer 59

• Lozenge
• Rapid absorption
• Onset 5-10 minutes
• Good for incident pain
• Dose is not dependent on MEDD

Also can be given :

• sl
• nasal fentanyl spray (esp for kids)

Question 60

When should opioid therapy be initiated?

Answer 60

• moderate or greater pain
• regardless of mechanism (neuropathic, somatic, visceral)
• dose titration until analgesia or side effects

Question 61

Buprenorphine

Answer 61

• PARTIAL mu agonist
• true partial mu agonist
• ceiling effect in higher doses
• oral not effective as all elimated in first pass metabolism
• injectable, sl, patch
• single doses of 0.3 mg iv are equal to 10-15 mg morphine IM
• LONG duration of action (6-9 hours)
• onset 30-60 minutes

Question 62

Nalbuphine

Answer 62

• mixed agonist-antagonist
• produce analgesia in opioid naive, but withdrawal in people already dependent on opioids
• mu ANTAGONIST, and kappa AGONIST
• Not useful for repeated dosing for pain, limited role
• low incidence of euphoria or respiratory depression
• useful for opioid induced pruritis

Question 63

Factors to consider when selecting an opioid

Answer 63

1. Pain severity
   * opioid vs non-opioid
2. Pharmacokinetic formulations

• start with a shorter half life opioid
• oral route if possible, or IV/sc

3. Co-existing disease

• renal impairment
• hepatic impairment

4. Response to previous opioids

Question 64

Rectal administation

Answer 64

• morphine, hydromorphone, oxycodone
• may be different from oral admin
• bioavailabilty might be different
• bypasses first pass hepatic metabolism

Question 65

Parenteral administation

Answer 65

• Bolus effects:
  
  • toxicity at peak concentration
  • breakthrough pain at trough concentrations
• IV bolus most rapid onset, depends on lipid solubility

Question 66

Epidural / Intrathecal dosing

Answer 66

• opioid receptors present in dorsal horn of spinal cord
• Epidural 1/10 of MEDD
• Intrathecal 1/100 MEDD (or 1/10 of epidural dose)

Question 67

Sublingual administration

Answer 67

• bioavailability poor with less lipophilic drugs
• works for SL fentanyl, buccal methadone, buprenorphine

Question 68

Scheduling opioids

Answer 68

1. Around the clock

• start low and go slow
• IR formulations, then SR
• Morphine 5 mg po q4h, HM 1mg po q4h, oxycodone 2.5 mg po q4.

2. Breakthrough dosing

• q1h po or q30 min IV/sc
• usually same as regular opioid (except methadone and fentanyl
• 10% daily dose
• or 1/6 of 4 hourly dose of opioid (ie same as 4 hourly dose)
• If more than 3 breakthrough doses/day, consider titration of base opioid

Question 69

Titration

Answer 69

• log linear increase in analgesic compared to dose
• escalations of < 30-50% are not likely to improve analgesia significantly

Question 70

Opioid tolerance

Answer 70

• Tolerance to analgesic effect:
  
  • need for increasing doses to maintain same effect in the abscence of other factors that would explain increase in pain.
• true tolerance is less common than disease progression or psychological distress
• true tolerance is from changes at receptor level.
• Tolerance to side effects varies:
  
  • Respiratory depression, somnolence, nausea RAPID tolerance
  • Constipation SLOW Or NO tolerance

Question 71

List side effects of opioids that resolve quickly (tolerance develops rapidly)

Answer 71

• somnolence
• nausea/vomiting
• respiratory depression
• urinary retention

Question 72

Opioid Rotation

Answer 72

• dose reduction of 25-50% for incomplete cross tolerance
  
  • to reduce toxicity, overdose, and minimize underdosing.
• Always done to reduce opioid side effects.
• Usually improves :
  
  • cognition
  • delirium
  • sedation
  • myoclonus
  • nausea/vomiting

Question 73

List common opioid adverse effects

Answer 73

Gastrointestinal

• nausea/vomiting
• constipation

Autonomic

• xerostomia
• urinary retention
• postural hypotension

CNS

• sedation
• cognitive impairment
• hallucinations
• delirium
• respiratory depression
• myoclonus
• seizure
• hyperalgesia

Cutaneous

• Itch
• sweating

Endocrine

• hypogonadism
• impaired adrenal hormones - blunted stress reponse
• obesity - diabetes

Question 74

List factors that predict opioid adverse effects

Answer 74

• Drug related
  
  • fentanyl less constipating
• Route related
• Patient related
  
  • age
  • renal function (M6G)
  • hepatic function
  • Other drugs
• Dose related
  
  • CNS side effects increased with increased dose
  • GI effects weaker dose reponse
  • constipation universal and not related to dose

Question 75

Approach to treating adverse effects

Answer 75

• Rule out other causes of adverse effects
• Then consider

1. Dose reduction 25%

• if pain is well controlled
• use of non opioids or adjuvants
• targeted therapy : radiation, chemo, surgery
• regional anesthesia, blocks, etc

2. Specfic therapies to treat AE
3. Opioid rotation
4. Change route

• switching routes from po to sc may help
• poor evidence

Question 76

Differential diagnosis of opioid adverse effects : delirium/drowsiness/cognitive impairment

Answer 76

CNS:

• mets
• leptomeningeal disease
• CVA
• extradural bleed

Metabolic

• dehydration
• hyper CA
• Hyper/hypo NA
• Renal failure
• hepatic failure
• hypoxemia

Sepsis/infection

Iatrogenic

• tcas
• benzos
• NSAIDS
• chemo/rads

Question 77

Differential diagnosis of opioid adverse effects : nausea/vomiting and constipation

Answer 77

Bowel obstruction

Medications:

• antibiotics
• vinca alkaloids (constipation)
• Flutamide (constipation)
• NSAIDS
• chemo/rad (nausea and vomiting)

Metabolic

• hyper Ca
• Hyper/hypoNA

Question 78

Management of opioid induced constipation

Answer 78

• prophylactic laxative (PEG, senna)
• does not improve with time
• avoid bulk laxatives
• methylnaltrexone

Question 79

Management of opioid related nausea and vomiting

Answer 79

• Often resolves over days-week
• opioids stimulate CTZ, delay gastric motility, delayed emptying
• either prn antiemetic effective at CTZ (prokinetic)
• scheduled prokinetic if nausea persistent

Question 80

Management of confusion and delirium related to opioids

Answer 80

1. Discontinue all non essential centrally acting medications
2. If analgesia satisfactory, reduce opioid dose by 25%
3. Exclude sepsis
4. Exclude CNS tumour involvement
5. If delirium persists, consider neuroleptic, rotation, change in route, different analgesic options.

Question 81

Management of sedation related to opioids

Answer 81

• sedation typical wehn beginning opioid therapy or dose increase
• tolerance within days to weeks
• limited evidence to treat with methylphenidate if persistent
• rotation may help
• opioid sparing adjuvants (rads, interventional)

Question 82

Respiratory depression related to opioids

Answer 82

• can be early indicator of CNS toxicity
• tachypnea and anxiety never related to opioids
• tolerance develops rapidly
• respiratory depression can occur if pain eliminated suddenly (neurolytic, epidural)

High risk

• rapid titration
• high dose
• pre -existing underlying lung disease
• multiple opioids given suddenly

Management:

• supportive with 02
• naloxone with caution, Titrate to RR
• naloxone infusion if long acting
• if peak effect already reached and patient bradypneic but rousable, can simply hold next dose and monitor

Question 83

Naloxone

Answer 83

• pure mu antagonist, displaces opioids at receptor
• IV/IM/SC/intranasal
• Dosing:
  
  • IV/SC/IM 0.4-2.0 mg single dose –> withdrawal
  • 0.02-0.2 mg for patients with opioid tolerance/dependence IV/SC/IM
  • 20 ug IV push
• Continuous infusion
  
  • 2/3 of effective bolus dose given hourly
  • 0.25-0.6 mg/hour

Question 84

Myoclonus from opioids

Answer 84

• can be normal, very common
• If distressing/frequent, consider dose reduction or rotation
• can treat with benzo (clonazepam) or gabapentin

Question 85

Hypogonadism secondary to opioids

Answer 85

• chronic opioids inhibitis HPA axis
• interferes with GnRH
• lower levels of LH and FSH
• clinical presentation:
  
  • fatigue
  • muscle wasting
  • Erectile dysfunction
  • reduced libido
  • menstrual changes
  • vaginal dryness
• Can consider HRT

Question 86

Metabolism and opioids

Answer 86

• Weight gain
• Hyperglycemia
• Worsening DM
• Central action of sympathetic nervous system and impaired insulin secretion

Question 87

Urinary retention and opioids

Answer 87

• Opioids increase smooth muscle tone
• bladder spasm or urinary retention
• increased sphincter tone
• Tolerance develops rapidly
• cath prn

Question 88

Opioid induced hyperalgesia

Answer 88

• paradoxical increase in reported pain with increasing or high doses of opioids
• central sensitization
• Management:
  
  • dose reduction
  • opioid rotation
    
    • genetic variation in opioid respose
    • differentia binding at receptor subtypes
  • NMDA antagonist (methadone), etc

Question 89

Opioids and driving

Answer 89

• provincial guidelines
• no driving while dose is titrated or initiated
• once sedation has resolved and dose stable, may resume driving
• self assessment by patient

Question 90

Opioid Allergy

Answer 90

• morphine and other opioids can induce histamine release from cutaneous mast cells (asthma, urticaria)
  
  • pseudoallergy and adverse effect
  • rarely life threatening
  • commonly morphine, codeine, meperidine
  • rare : fentanyl, sufentanil, tramadol
• True allergy rare (< 2%). IgE mediated:
  
  • anaphylaxis
  • urticaria
  • EM
  • severe hypotension
  • bronchospasm, edema
  • angioedema
• difficult to distinguish, testing challenging
• assume likely pseudoallergy
• can switch to another class with less histamine release
• concurrent H1/H2 blocker can be considered

Question 91

Opioid misuses and addiction

Answer 91

• Abuse :
  
  • intentional self adminstration of medication for non medical purpose or use of illegal drug
• Addiction:
  
  • primary chronic disease
  • impaired control over drug use, compulsive use despite harm, craving.
• Risk of developing addictive behaviours with medical use of opioids for palliative care needs is low
• We overestimate risk of addiction
• confuse physical dependence and addiction
• reluctance to prescribe and use them

Question 92

Therapeutic dependence

Answer 92

• Patient require a specific drug to control a disease process or symptom are dependent on therapeutic efficacy of drugs in question.

Question 93

Psychological dependence

Answer 93

• effects mediated in CNS most likely to lead to misuse.
• continued craving and abherrent drug seeking behaviour
• use despite harm to self or others

Question 94

Physical dependence and Withdrawal

Answer 94

• withdrawal when abruptly discontinued or opioid antagonist administered.
• Withdrawal:
  
  • anxiety
  • irritability
  • chills/hot flashes
  • salivation, lacrimation, rhinorrhea, sneezing, sweating
  • nausea
  • abdo cramping
  • insomnia
• Time course of withdrawal function of half life of opioid
• Abstinence sx within 6-12 hours, peak at 24-72 hours for short acting opioids
• Sx onset 36-48 hours for long acting (methadone)
• must decrease / taper dose.
• usual daily dose to prevent withdrawal if 75% of previous daily dose

Question 95

Pseudoaddiction vs addiction

Answer 95

• pseudoaddiction :
  
  • intense concern about availablity of opioids an drug seeking behaviour
  • resolves once pain is relieved with dose escalation
• addiction
  
  • does not resolve.

Question 96

Screening for misuse and abuse risk

Answer 96

• all patients should be screened
• validated tools (self report) : SOAPP, COMM
• require multidisciplinary team to manage