Opioids.

Opioids

Definitions Opium: Dried latex from the opium poppy Papaver Somniferum
Opioid: Natural or synthetic pharmaceutical which has an affinity to the opioid receptor Opiate: natural alkaloid product of opium Morphine, Codeine, Papaverine Narcotic: traditionally referred to opioids but more of a legal term for drugs of addiction/abuse

Background Opium used by humans since the stone age
Opos: Greek for “juice” Mentioned in many ancient texts for various medicinal uses Beneficial (analgesia, hypnotic) and harmful (resp depression, addiction) well known for centuries

Brief Opioid History Opium poppies sprung from the tears of Aphrodite when she mourned for her beloved Adonis.

Brief Opioid History Opium is obtained from the exudate of seed pods of the poppy Papaver somniferum

Brief Opioid History Opioids used for the treatment of pain for thousands of years

Brief Opioid History 3rd century BC - 1st reference of poppy juice (opium) Paracelsus formulated Laudanum Sertuener isolated ‘soporific principle’ in opium (opium alkaloid) isolated alkaloid named morphine mid 1800’s - medical use of pure alkaloids began to spread, morphine widely used to treat wounded soldiers during the American Civil War meperidine (phenylpiperidine derivative) was the 1st totally synthetic opioid produced fentanyl synthesized (4-anilinopiperidine derivative; derivative of normeperidine) development of more potent opioid sufentanil and then alfentanil first descriptions of remifentanil

Mechanism of Action Opioids produce affects by activating opioid receptors Opioid receptors highly concentrated in CNS: Tractus solitarius Peri-aqueductal gray midbrain Cerebral cortex Substantia Gelantinosa spinal cord Also found in Peripheral nerves

Opioid receptors Coupled with inhibitory G-Proteins Agonism leads to:
Closing voltage sensitive Ca++ channels Stimulation K+ influx (hyperpolarization) Reduced cyclic AMP Reduced neuronal cell excitation and transmission

Mechanism of Action Directly inhibit ascending transmission of nociceptive information in spinal cord dorsal horn (Substantia Gelantinosa) Mechanism of euphoria unclear but thought to involve dopaminergic pathways in nucleus accumbens

Opioid Receptors and Effects
MOP (mu) mu 1: analgesia, physical dependence mu 2: resp Depression, miosis, euphoria, dependence, reduced GI motility mu 3: vasodilation KOP (kappa) analgesia, sedation, miosis, dysphoria DOP (delta) analgesia, antidepressant, convulsant, dependence NOP (nociceptan) anxiety, depression, tolerance

Opioid Effects - CNS Analgesia Sedation Best for visceral pain
Less effective for somatic pain Poorly effective for neuropathic pain Sedation Mental cloudiness Can induce sleep, possibly because of relief of pain Not amnestic

Opioid Effects - CNS Euphoria and Dysphoria Hallucination
In absence of pain may cause dysphoria Hallucination More common with kappa agonists Tolerance and Dependence May be due to down regulation of receptors Withdrawal phenomenon: Restlessness, irritability, salivation, N/V, diarrhea, muscle cramps, sweating Not fatal but may be dangerous for cardiac patients due to sympathetic stress

Opioid Effects - CNS Mild decreases in Cerebral Metabolic Rate
Mild decrease in ICP Little or no effect on Cerebral Blood Flow Muscle Rigidity More common with high dose / potent opioids Prevented / attenuated with muscle relaxants

Opioid Effects - Cardiovascular
Less effects on CVS than other anesthetic drugs More stable at high doses Mild bradycardia Peripheral vasodilation due to histamine release Decrease pre-load Used at high doses in “cardiac anesthesia”

Opioid Effects - Respiratory
Respiratory Depression (mu receptor) Resp. rate decreases more than Tidal Volume Decreased brainstem sensitivity to CO2 Exacerbated with addition of other anesthestics Suppression of cough reflex Blunt response to intubation

Opioid Effects – GI tract
Stimulation of Chemoreceptor trigger zone Nausea and Vomiting Use of opioids as risk for Post-op N/V Increases pressure in biliary tract (exception: meperidine) Decreased GI tract motility Constipation

Opioid Effects - Other Endocrine: Ocular: Obstetric
Blunt stress response (decrease cortisol, ACTH) Ocular: Miosis Obstetric All opioids cross the placenta Chronic use by mother can result in neonatal withdrawal No known teratogenic effects

Balanced Anesthesia Balance of agents and techniques to produce different components of anesthesia Analgesia Amnesia Muscle Relaxation Abolition of Autonomic responses Homeostasis

Balanced Anesthesia Use of Opioids in a balanced anesthetic:
Reduces post-op pain Reduces post-op anxiety Decrease autonomic and somatic responses Hemodynamic stability Decrease requirements for volatile agents Decrease requirements for IV anesthetics (propofol)

Pharmacokinetics Opioids are weak bases
In plasma they dissociate into ionized and unionized fractions depending on pKa Unionized fracture is more freely diffusable Poorly absorbed from acidic stomach (ionized +++) Readily absorbed from small intestine

Pharmacokinetics Lipid solubility Protein binding
First pass metabolism pKa and ionized/unionized fraction

Metabolism Mainly metabolized by the Liver
Active and inactive metabolites Morphine Meperidine Kidneys involved in conjugation of Morphine

Commonly used Opioids Agonist/Antagonists Antagonists Pure Agonists
Morphine Codeine Hydromorphone Fentanyl Meperidine Remifentanil Alfentanil Sufentanil Methadone Agonist/Antagonists Pentazocine Buprenorphine Antagonists Naloxone Naltrexone

Morphine Gold standard opioid / Natural product MOP receptors
Usual doses mg/kg IM 1-5mg IV Hydrophilic Slower peak onset, extended duration of action Long duration of action intrathecal/epidural 12-24hrs Peak onset IM : mins IV : 10 minutes Use caution in renal impairment as Morphine-6-Glucuronide accumulates

Codeine Natural opioid Is a pro-drug, requires metabolism to morphine
Commonly used PO but can be given IM Unpredictable conversion 1% over metabolize 10% under metabolize This has resulted in deaths Certain drugs affect enzymatic conversion Decrease: paroxetine, fluoxetine, bupropion benadryl. Increase: dexamethasone, rifampacin Not commonly used in Anesthesia, falling out of favour in pain management

In contrast to morphine, codeine is about 60% as effective orally as parenterally. The greater oral efficacy is due to less 1st pass metabolism in the liver. However, Codeine has exceptionally low affinity for opioid receptors and the analgesic effect of codeine is due to it’s conversion to morphine (O-demethylation, about 10% of codeine is O-demethylated to morphine). The conversion of codeine to morphine is effected by the cytochrome P450 enzyme CYP2D6. Well characterized genetic polymorphisms in this enzyme lead to the inability of convert codeine to morphine, thus making codeine in-effective as an analgesic for about 10% of the Caucasian population(Eichelbaum and Evert, 1996). Other polymorhisms can lead to enhanced metabolism and enhanced effect. Ref(Goodman and Gilman 10th ed pg 589

Fentanyl Synthetic, 100x more potent than morphine
IV, IM, transbuccal, transdermal, neuraxial Peak onset 2-3 minutes IV Used as induction agent 2-3mcg/kg IV Boluses mcg/kg Spinal mcg Epidural mcg Highly lipid soluble / large Vd Short duration after bolus due to redistribution Long context sensitive half-time with infusion Improves onset and quality of block in Spinal and Epidural

Hydromorphone (Dilaudid)
Semi-synthetic mu agonist 5X as potent as morphine PO, IV, IM, SC, Intrathecal, Epidural More lipid soluble than morphine More water soluble than fentanyl Safer in renal impairment

Meperidine (Demerol - Pethidine)
First synthetic opioid, approx 1/5 potency of morphine Mu and kappa action Local anesthetic properties Can be used as a single agent for spinal anesthesia Unique properties Decrease spasm in sphincter of oddi Blocks sodium channels (local anesthetic action) Results in tachycardia due to muscarinic blockade Useful to stop shivering response Downsides: Metabolites have a long half-life and can cause seizures and accumulate in renal failure Less commonly used now than in the past

Remifentanil Ultra-short acting, synthetic, highly potent opioid
200X potent than morphine Independently metabolized by Plasma esterases due to ester linkage Useful as an infusion when deep opioid effects required but rapid recovery desired Used for sedation, GA, TIVA Usual dose mcg/kg/min Context sensitive half-time 6 minutes Bradycardia, hypotension, muscle rigidity more common Can be used as a co-induction agent “Rem-tubation” Can result in opioid induced hyperalgesia No residual effects thus need another opioid post-op

Pentazocine Partial antagonist/agonist Approx ¼ potency of morphine
IM, SC (less often) IV and PO Mostly action on kappa receptors More likely to cause nausea, bizarre dreams Less respiratory depression May provoke withdrawal in opioid dependent patients Less effective for severe pain

Naloxone Pure antagonist at all opioid receptors
Reverses respiratory depression Resuscitation doses mg In peri-operative patient these doses may result in severe pain crisis Small titration doses mg Effective antagonism 30 minutes May need re-dosing for longer acting drugs

Opioids in the OR Important part of a balanced anesthetic
Decrease MAC Patient comfort Blunt stress response – better outcomes Stable Hemodynamics The trick is to have an appropriate levels to correspond to the varying stimulation levels of the surgery Need to anticipate pain control post-op Want patient to “wake up” comfortably but also want him to “wake up” in a timely manner

Opioids in the OR Opioids have many downsides
Constipation Delay bowel recovery Nausea & vomiting Hallucination Co-analgesics and regional anesthetic techniques spare their use

Opioids in the OR Often given at induction for intubation
PRN Bolus therapy Need to anticipate stimulating parts of surgery and “top up” as required Keep in mind peak onset Morphine 10 minutes Fentanyl 2-3 minutes Background infusions useful Fentanyl, sufentanil, hydromorphone, morphine

Opioids in the OR Unreliable as a single agent Not amnestic
Used in conjunction with other agents Dose dependent decrease in MAC for volatile agents Blunt stress/sympathetic responses to pain and intubation

Opioids in the OR Can be given a loading dose with intermittent boluses Continuous infusion Pay attention to Context sensitive half-time Post-op analgesia Part of a “Balanced Anesthetic” Smooth out extubation

Context Sensitive Half-time
Time for blood levels to decrease by half after a continuous infusion is discontinued “Context” is the duration of the infusion Very high for drugs with a large Vd due to accumulation and redistribution Fentanyl, Sodium-thiopental

Opioids in Acute Pain Main ingredient in multi-modal analgesia
Traditional approach of IM/SC boluses less effective than IV PCA Avoid peaks/troughs

What is the “Best Way” to manage acute post-operative/trauma pain?
FIRST, DO NO HARM Therefore, the “best way” is a BALANCE Effective Analgesic Modalities Patient Safety

KEY POINTS “Emphasis is placed on the utilization of a multimodal analgesic approach to maximize analgesia while minimizing side-effects.” Transduction Transmission Modulation Perception There is as of yet no single silver bullet!! Safety means avoid side-effects. Emphasis is placed on the utilization of a multimodal analgesic approach to maximize analgesia while minimizing side-effects.” The 4 basic “target areas” within the nervous system where various drug modalities may act to diminish conversion of nociception to actual realized pain are: transduction, transmission, modulation and perception.

Acute Pain Management Modalities
Cyclo-oxygenase inhibitors Non-specific COX inhibitors(classical NSAIDs) Selective COX-2 inhibitors, the “coxibs” Acetaminophen is probably COX-3 Opioids Local Anesthetics NMDA antagonists Ketamine, dextromethorphan COX-inhibitors affect transduction and modulation. Opioids modulation and perception. Local anesthetics affect transmission and NMDA antagonists affect modulation.

Analgesia with Opioids alone
The harder we “push” with single mode analgesia, the greater the degree of side-effects Side-effects There is no single silver bullet that is able to provide adequate analgesia in moderate to severe pain conditions in all patients. Analgesia

Multi-modal Analgesia
“With the multimodal analgesic approach there is additive or even synergistic analgesia, while the side-effects profiles are different and of small degree.” There is no single silver bullet. Side-effects Analgesia

The rationale for COX-Inhibitors in acute pain management
The problem with the “Little Pain – Little Gun, Big Pain – Big Gun Approach” With opioids, analgesic efficacy is limited by side-effects “Optimal” analgesia is often difficult to titrate >10 – fold variability in opioid dose:response for analgesia in opioid naïve patients! factors add to the difficulty Opioid tolerance, anxiety, obstructive sleep apnea, sleep deprivation, concomitantly administered sedative drugs The problem we get into with going straight to opioid analgesia for moderate-severe to severe or excruciating pain is that we usually get into some nasty side-effects. Frequently we can’t even attain satisfactory analgesia on account of dose limiting complications. The state of “morphine-failure”, when the patient is oscillating between the state of over-sedation and writhing in acute pain. However, the foundation of non-opioid analgesia provided cox-inhibitors works in wonderful concert with the opioid analgesics. Greater analgesia is attained with fewer opioid side-effects ( the opioid sparing effect). This idea of adding a cox-inhibitor to a patient already receiving and perhaps even failing analgesic therapy with a powerful opioid, is quite difficult for some patients and even doctors to grasp. “What’s the point of adding a little gun, if the big guns are not even working?? Patients have to be educated that these drugs from different classes work together, the analgesic result being greater than the sum of the individual parts and with less side-effects too! A useful analogy that patients and maybe even surgeon find easy to understand is using the “opening of a door” as a model of analgesic efficacy. Morphine can blow the door open but it can’t activate the door handle very well. The COX-inhibitor is adept at activating the door handle but can only open the door partially. Working together they can open the door wide open much more easily and with less potential for collateral damage.

The rationale for COX-Inhibitors in acute pain management
The problem with the “Little Pain – Little Gun, Big Pain – Big Gun Approach” Patient Safety!! If the “Big Gun” is failing due to dose limiting sedation/respiratory depression, the addition at that time of the “Little Gun” may kill the patient.

Opioids Pharmacokinetic + Pharmacodynamic
patient to patient variability results in1000 % variability in opioid dose requirements Concept # 1 opioid dosage must be individualized therefore, if parenteral therapy indicated, IV PCA much better suited to individual patient needs than IM/SC

Patient Controlled Analgesia with Intravenous Opioids
IV PCA: morphine golden standard, pruritus a common problem meperidine a little faster onset than morphine normeperidine a toxic metabolite is a problem for patients with decreased renal function or using large dosages for more than a few days hydromorphone less confusion in elderly patients?

Opioids Issue With parenteral opioids the patient may experience intolerable side effects before adequate analgesia is attained

Opioids CONCEPT # 2 Targeted regional administration of opioid
results in enhancement of the therapeutic index (ratio of analgesia/side effects) Opioids can be administered directly into lumbar CSF or epidurally for enhanced analgesic effects.

The proper use of oral opioids
The limitations of combination drugs Codeine is a “pro-drug” Potent oral opioids are under-utilized Offer “around the clock” not “prn” In stable situations long acting, slow release formulations may be indicated The principles to proper use of oral opioids require an understanding of the above.

Opioids *Cancer Pain Monograph (H&W, 1984)
CONCEPT # 3 Under utilization of high efficacy PO opioids PO opioid equivalence of 10 mg morphine IM/SC * morphine 20 mg codeine 120 mg hydromorphone 4 mg meperidine 200 mg oxycodone 10 mg The three most frequently used potent PO opioids are morphine, hydromorphone(Dilaudid) and oxycodone(active opioid in Percocet and Oxycontin and Oxy-IR). Note listed amounts are equivalent to twice opioid activity of two T#3. Meperidine PO equivalent is listed to emphasize it lack of potency via the oral route. It is associated with high rate of S/E due to toxic metabolites and is not recommended.

homeopathic dose ---- potentially lethal
Opioids Dilaudid 1 – 4 mg PO/IM/IV Q4H prn NOT! This represents up to 30 fold range in peak effect in any given patient 1 mg PO mg IV bolus homeopathic dose ---- potentially lethal PO to IV conversions are based on total daily equivalents. They do not take into account the more rapid onset of action via the IV bolus route, leading to a greater peak effect. This is especially true of the more lipophyllic drugs like HM and demerol compared to morphine. Therefore 4 mg IV is equivalent to 4X4 = 16 PO but the peak effect is at least double I.e. 32mg.

Opioids: Rational multi-route orders?
Foundation of Acetaminophen/COX-inh. Morphine mg PO Q4h prn Morphine mg s.c. Q4h prn Morphine 1-2 mg IV bolus Q1h prn Hydromorphone mg PO Q4h prn Hydromorphone 0.5 – 1 mg s.c Q4h prn Hydromorphone 0.25 – 0.5 mg IV Q1h prn

NMDA Receptor Antagonists - To prevent or reverse “pathological” acute pain
Ketamine, Dextromethorphan Ketamine is widely known as a dissociative “general anesthetic” - 3 mg/Kg IV bolus Ketamine mg/kg IV with induction of general anesthesia has pre-emptive analgesic effects - less pain and less opioid use post-op Ketamine mg IV bolus for analgesia in post-surgery/ trauma patient - Ketamine as co-analgesic - combined 1:1 with morphine IV PCA. Better analgesia, less S/E Dextromethorphan 45 mg PO Q12H

The New Challenges in Managing Acute Pain after Surgery and Trauma
The Opioid Tolerant Patient The greatest change in pain management practice/attitudes in the last 10 years is the now wide spread acceptance of the use of opioids for CHRONIC NON-MALIGNANT PAIN Renders the “usual” standard “box” orders totally inadequate in these patients Demerol 75 mg IM Q4H prn or Tylenol #3 just isn’t going to cut it!

Duration of analgesic effect
Opioid Half-life Onset Duration of analgesic effect Fentanyl IV: 2 – 4h Patch: 17h IV: within minutes Patch: 12-24h IV: 0.5 – 1h Patch: 72h Hydromorphone (Dilaudid) 2 – 3h IV: min PO: 30 min 3 – 5h Methadone** 8 – 59h 30 – 60 min 4 – 8h Morphine 2 – 4h IV: min PO (IR): min IR: 3 – 6h SR: 8 – 12h Meperidine (Demerol) 3 - 5h (15-30h for metabolite) 10 – 45 min Codeine 3 – 4h 4 – 6h Oxycodone IR: 2 – 5h SR: 5h 15 – 60 min SR: 12h Hydrocodone 10 – 60 min Table compares some of the PKS All have similar t1/2 and onset (except for methadone) Duration of analgesic effect helps determine proper dosing frequency IV fentanyl Methadone: long-acting product**half-life can be long but analgesic effect lasts 4 – 8 h

Opioid Usual Starting Dose Comments
Fentanyl* 25 – 100 mcg IV q1h, then 1 – 2 mcg/kg/h Patch: NOT for acute pain & NOT for opioid-naïve pts; do not cut patch in half Hydromorphone (Dilaudid) 0.5 – 1 mg q4h IV 1 – 2 mg q4h PO Very potent; preferred in pts with renal impairment Methadone 5 mg q8-12h PO Monitor for QT prolongation & drug interactions Morphine 2 – 5 mg q4h IV 5 – 10 mg q4h PO (IR) 15 – 30 mg q8 or 12h (SR) MSContin: NOT for acute pain; do not split/crush tablets Meperidine (Demerol) 50 mg q3-4h PO/IV NOT recommended for chronic use Codeine 30 – 60 mg q4h PO Has more side effects than morphine Oxycodone 5 mg q4h PO (IR) 10 – 20 mg q12h (SR) OxyContin: NOT for acute pain; do not split/crush tablets Hydrocodone 5 – 10 mg q4h PO always combined with APAP or ibuprofen – which limits its dosing **fentanyl: different indications (adjuvant for general anesthesia maintenance, minor & major surgical procedures, control of post-op pain Fentanyl patch dose will vary MSContin & OxyContin dose will vary depending upon narcotic requirement MSContin can be dosed q8 to q12h Codeine has more side effects than morphine – more nausea and constipation

Case Problem: Inadequate Analgesia with IV PCA after Open Cholecystectomy
45 yr. female c/o severe pain at rest and difficulty breathing due to incisional pain- 4 hrs. post-op IV PCA morphine: 1mg bolus, 5 min. lock-out 150 demands : 28 good has stopped using PCA because, “it is making me sick(N/V) and it’s not working” received 25 mg gravol X 2 one hour ago which helped just a little with the N/V, but did make her quite groggy Solution? “Between a rock and a hard place!” as far as the use of opioids goes. This case illustrates how most practitioners utilize the cox-inhibitor group.

Case Problem: Inadequate Analgesia with IV PCA after Open Cholecystectomy
Problem: Patient unable to attain required morphine blood level due to intolerable side-effects (N/V, sedation) Solution: Administer COX-inhibitor Toradol IV/IM or Naproxen 500 mg PR Q12H, this may be changed to 250 mg PO TID with meals once eating Control N/V Stemetil, Ondansetron, Decadron May need to consider changing opioid i.e. Demerol Local Anesthetics: intercostals, paravertebral, epidural

Case #2 53 Year old male Post-op Open Right Hemicolectomy x 45 minutes
Previously healthy except for Colon Cancer Called by PACU for decreased level of consciousness What do you do?

Case #2 Apply standard monitors/IV access/Oxygen
What are you next options? Treat and investigate concurrently Call for airway equipment/assistance

Case #2 History Get vital signs Physical Exam
Review anesthetic and PACU record Given injection of morphine 15 minutes prior Previously healthy No allergies Uneventful GA Reversal given, patient awake and comfortable and transferred to PACU Get vital signs HR 64 BP 110/70 RR 5 SPO2 88% T35.8C Physical Exam GCS 8 Pinpoint Pupils Wound dry/OK

Decreased LOC in PACU & Delayed Emergence
H’s T’s Hypovolemia Vitals, Wound check, HGB Hypothermia Vitals Hypo/Hyper glycemia Glucometer Hypoxia SPO2, ABG Hyper/Hypo Kalemia ECG, ABG Hydrogen Ion ABG Tablets/Toxins Opioids- Vital, Pupils Ketamine Muscle Relaxants - TOF Thrombosis PE Stroke Tamponade Tension PTX Trauma

Actions to take: Take control of the situation, call for help
Oxygen, IV, Monitor ABCs A: Jaw thrust, OPA, LMA, ETT B: PPV if necessary C: Fluid bolus if necessary, pressor Discontinue Anesthetic infusions DON’T D: Dextrose O: Oxygen N: Naloxone , Neostigmine, Flumazinil T: Thiamine

Drug Antidotes Naloxone Flumazinil Antidote for Opioid intoxication
Rapid onset (within minutes) In post-op patients avoid large doses Pain crisis may occur with limited ability to treat 1 Vial (0.4mg) diluted to 10cc Give 0.04mg-0.08mg (1-2cc) increments Flumazinil Antidote for benzodiazepine Give in 0.2mg increments Caution: may provoke seizures

Case 2 Continued Give Naloxone 0.4mg IV
Patient awakes and begins to complain of severe severe pain Vitals: 160/80 HR 110 SpO2 98% GCS 15 Begins to develop chest pain What do you do now?

ECG Shows

Next steps? Oxygen, IV, Monitors Analgesic Block stress response
Naloxone will block effects of morphine ASA Ketamine Acetominophen Ketorolac Block stress response B Blocker Decrease Pre-load NTG Sublingual/IV

Patient Loses Consciousness

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