Chapter 11 Major Opioids in Pain Management Flashcards
KEY POINTS 1. With an informed and cautious approach, opioids may be safe and effective for treating moderate to severe pain of both malignant and nonmalignant origin. 2. Clinicians who choose to offer chronic opioid therapies must formulate rational and individualized regimens according to strategies such as those described by the FSMB and the APS/AAPM consensus guidelines. 3 Safe opioid therapy requires a program for continuous and close observation of analgesia and possible adverse effects
Adverse Effects of Opioid
sedation, respiratory suppression, nausea and vomiting
An attempt to optimize a patient’s pain management may include concurrently combining opioids with
nonopioid adjuvant analgesics (nonsteroidal anti-inflammatory drugs [NSAIDs], acetaminophen, antidepressants, anticonvulsants, etc.), physical therapy, psychological therapy, and/ or injection therapies
Health-care professionals tend to use opioid therapy as a second-line treatment for chronic non-malignant pain (CNMP) for the following reasons
(1) nonopioid medications, such as NSAIDs and anticonvulsants or tricyclic antidepressants, can be efficacious in treating CNMP secondary to arthritic pain and neuropathic pain respectively;
(2) injection therapies may be effective and obviate the need for opioids; and
(3) considering the noteworthy side effects and liability profiles of opioid treatment, the risk-benefit ratio often demands that alternative treatments be implemented before instituting COT
In instances where tolerance is suspected, methadone may offer extra benefits in treating neuropathic pain because
of its N-methyl-d-aspartate (NMDA) receptor blocking action that may reduce tolerance to opioids as well as provide analgesia
Acute Pain
Acute pain is the normal, predicted physiologic response to a noxious chemical, or thermal or mechanical stimulus, and typically is associated with invasive procedures, trauma, and disease. It is generally time-limited.
Addiction
characterized by behaviors that include: impaired control over drug use, craving, compulsive use, and continued use despite harm.
Chronic Pain
Chronic pain is a state in which pain persists beyond the usual course of an acute disease or healing of an injury, or that may or may not be associated with an acute or chronic pathologic process that causes continuous or intermittent pain over months or years
Pain
An unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage
Physical Dependence
Physical dependence is a state of adaptation that is manifested by drug class-specific signs and symptoms that can be produced by abrupt cessation, rapid dose reduction, decreasing blood level of the drug, and/or administration of an antagonist.
Pseudoaddiction
The iatrogenic syndrome resulting from the misinterpretation of relief-seeking behaviors as though they are drug-seeking behaviors that are commonly seen with addiction. The relief-seeking behaviors resolve upon institution of effective analgesic therapy
Substance Abuse
Substance abuse is the use of any substance(s) for non-therapeutic purposes or use of medication for purposes other than those for which it is prescribed
Tolerance
Tolerance is a physiologic state resulting from regular use of a drug in which an increased dosage is needed to produce a specific effect, or a reduced effect is observed with a constant dose over time.
Codeine
Tylenol #2, 3, and 4 Acetaminophen/Codeine; Tylenol 1: (325 mg / 8 mg) Tylenol 2 (300 mg/15 mg), Tylenol 3 (300 mg/30 mg), Tylenol 4 (300 mg/60 mg).
Hydrocodone
Vicodin, Vicoprofen, Lortab, Lorcet, Norco, Hydrocet, and Zydone Hydrocodone/paracetamol, hydrocodone/acetaminophen, or hydrocodone/APAP (or under brand names such as Lortab, Norco or Vicodin)
Oxycodone
Percocet, Percodan, Endocet, Endodan, Roxicet, Roxicodone [OxyContin] The active ingredient in OxyContin is oxycodone but OxyContin (a brand name derived from "oxycodone continuous") has a time-release mechanism, which means the drug is released in the body over a period of time. Regular oxycodone is an immediate-release drug,
Oxymorphone
Opana
Hydromorphone
Dilaudid , Exalgo
Sustained-release versions of oral morphine
MS-Contin, Oramorph, Kadian, Avinza, Embeda
Candidate for opioid analgesics
A patient with moderate to severe acute and/or chronic pain who has not improved with nonopioid therapies
A patient with minimal to no recent opioid exposure should be given
a titration trial with a low dose Short Acting Opioid to establish his/her opioid requirement. Patients who are opioid naive may require test dosing that is most safely given “as needed.”
combination agents
codeine/acetaminophen, hydrocodone/acetaminophen hydrocodone/ibuprofen, oxycodone/acetaminophen, oxycodone/aspirin
combination agents drawbacks
(1) in a setting of suboptimal analgesia, attempting to maximize the opioid analgesic may simultaneously raise the nonopioid analgesic above its ceiling dose and into the toxicity range; (2) patients can develop tolerance to a drug with no ceiling effect while not developing tolerance to the other drug that does have a ceiling effect
What determines whether “as needed” (PRN, pro re nata) versus “around-the-clock” dosing is necessary
The severity and frequency of the patient’s pain
A “rollercoaster” effect
whereby patients have pain, take analgesics, experience brief periods of relief, followed by repetition of this cycle when the pain returns.
The usual goal of opioid administration for treatment of chronic pain
to achieve sustained analgesia over regular intervals
Fixed Dosing Intervals
a strategy permits consistent delivery for reaching steady-state levels and avoids the peak-and-trough effect associated with on demand dosing. fixed dosing avoids both the reinforcement of pain complaints and behaviors with additional analgesics as well as the precipitation of anxiety
Benefits of using an Long Acting Opioid Sustain Release Opioid
include achievement of safe, effective steady-state levels with regard to fixed dosing intervals and lack of a compounded nonopioid analgesic which may impose a ceiling dose.
Fixed Dosing with Long Acting Opioid Sustain Release Opioid
provide more sustained levels of analgesia, improved compliance, has less reward associated reinforcement of potentially dysfunctional cycles where pain and pain medication become a conditioned part of the patient’s life, and has a relative decreased risk of addiction or abuse
An intravenous (IV) or subcutaneous (SQ) infusion is commonly used
in cancer patients, often with around-the-clock dosing for constant effect. Both routes avoid the first-pass effect and can be supplemented by PRN doses for breakthrough pain
The SQ route advantages
including faster onset of analgesia compared with most oral preparations (although slower than IV), uncomplicated access in patients with poor venous access, and safer administration compared with the intramuscular route in patients with bleeding disorders or reduced muscle mass
Opioid patient-controlled analgesia (PCA)
morphine, hydromorphone, fentanyl
Alternatives for patients unable to use IV or oral preparations include
rectal (suppositories are available containing morphine, hydromorphone and oxymorphone), sublingual, buccal, intranasal, transdermal, epidural, and intrathecal routes of administration
The two critical issues related to treatment endpoints in COT (Chronic Opioid Therapy)
include defining what outcomes should be expected and followed to demonstrate an effective and safe trial of opioids, and determining when and how opioid therapy should be discontinued (or tapered) if the treatment is either effective or ineffective
Markers of opioid benefit in patients treated for CNMP include
subjective pain reduction and evidence of improved functional status and quality of life
Determination of a treatment failure requires consideration of multiple contributing factors, including
(1) underdosing; (2) inappropriate dosing schedule; (3) improper drug delivery route; (4) potentially diminished opioid responsiveness relating to the nature of the pain generator (e.g., neuropathic pain); (5) involvement of unresolved contributors to pain, such as physical, psychological, and social disability; and (6) development of side effects that limit dose escalation
Management of pain in tolerant patients
In such cases, opioids are slowly and incrementally increased until analgesia with tolerable side effects is reached
Analgesia occurring only in conjunction with intolerable side effects indicates
that the particular opioid is suboptimal, and there may be a need to change to a different opioid
Analgesia occurring only in combination with sedation after an individual trial of most or all opioids suggests
opioid-insensitive pain
Side effects without analgesia indicate
failure for that particular opioid
Meperidine (Demerol)
weak mu-opioid receptor agonist
Meperidine use in the pain management setting has steadily declined due to
potential for neurotoxicity. Meperidine has a relatively short half-life of 3 hr and prolonged administration (greater than 3 days) is problematic due to the potential for accumulation of its neurotoxic metabolite, normeperidine.
Meperidine compared to morphine
it is one-tenth as potent and has a slightly more rapid onset and shorter duration of action.
Meperidine compared to morphine at equianalgesic doses
meperidine produces less sedation and pruritus and may be more effective in neuropathic pain
Meperidine side effect
it possesses significant cardiac (orthostatic hypotension, and direct myocardial depression), anticholinergic, and local anesthetic properties, which decrease its therapeutic window
Unlike other opioids, epidural or spinal administration of meperidine can produce
sensory, motor, and sympathetic blockade
Meperidine does have a beneficial use in the operative setting for treatment of
postanesthetic shivering
Normeperidine
Meperidine is demethylated in the liver to normeperidine, which has a half-life of 12 to 16 hr and is well documented to produce central nervous system (CNS) hyperactivity and, ultimately, seizures. Since normeperidine is excreted by the kidneys, its adverse effects are most commonly, although not exclusively, seen in patients with renal impairment.
Normeperidine toxicity initially manifests
as subtle mood alteration and may progress to potentially naloxone-irreversible tremors, myoclonus, and seizures
Caution may be prudent in coadministering meperidine and…
for patients on monoamine oxidase inhibitors, coadministration of meperidine can have potentially fatal outcomes. Caution may be prudent in coadministering meperidine and any other serotonergic drugs such as selective serotonin reuptake inhibitors (SSRIs), tramadol, or methadone. Meperidine is a potent inhibitor of serotoinin reuptake into presynaptic neurons
Morphine
Morphine is the prototypical mu-opioid receptor agonist against which all other opioids are compared for equianalgesic potency
Morphine routes of administration
It can be given via oral, IV, epidural, or intrathecal routes for perioperative and postoperative pain management
Morphine formulations
As an SAO, it is available in IR formulations (morphine, MSIR, and Roxanol). As an SRO (MS-Contin, Oramorph-SR, Kadian, Avinza, Embeda), its dosing frequency ranges from every 8 to 24 hr
Embeda
contains both morphine and the opioid receptor antagonist naltrexone
Because of the delay in transport across the blood-brain barrier
morphine has a slower onset of action compared to other opioids
morphine analgesic effect plasma half- life
morphine has a relatively longer analgesic effect of 4 to 5 hr relative to its plasma half-life (2 to 3.5 hr), thereby minimizing its accumulation and contributing to its safety. The disproportional duration of analgesia versus plasma half-life is due in part to its low solubility and slower elimination from the brain compartment relative to the plasma concentration.
Morphine Toxicity
Although morphine’s pharmacologic activity is primarily due to the parent compound, morphine’s efficacious and toxic effects can also be mitigated or perpetuated by two of its major metabolites: morphine 3-glucuronide (M3G) and morphine 6-glucuronide (M6G).
Morphine 3-Glucuronide (M3G)
M3G lacks any mu- and delta-opioid receptor activity and accounts for approximately 50% of morphine’s metabolites. It has been shown in animals to cause generalized hyperalgesia, CNS irritability, seizure, myoclonus, and development of tolerance
Morphine 6-Glucuronide (M6G)
M6G is a mu- and delta-opioid receptor agonist and accounts for approximately 5% to 15% of morphine’s metabolites. M6G has intrinsic opioid agonism and sustains analgesia in addition to side effect
Morphine glucuronide concentrations by routes
Because the intravenous and rectal routes of administration avoid hepatic biotransformation, their glucuronide concentrations are less than with oral administration. Chronic use of oral morphine ultimately results in higher circulating concentrations of the glucuronides (mean ratios of M3G:M6G range from 10:1 to 5:1) than the parent compound
morphine’s elimination and excretion
morphine’s elimination is dependent on hepatic mechanisms, it should be used with caution in cirrhotic patients. Because morphine metabolites are excreted through the kidneys, the dose should be adjusted in those with renal impairment in order to minimize the risk of adverse side effects associated with the accumulation of glucuronide metabolites.
Morphine Side Effect
respiratory depression, sedation, and vomiting due to relatively high concentrations of M6G can be reversed by naloxone, the most concerning adverse effect in patients with compromised renal function is encephalopathy and myoclonus
Oxycodone
semisynthetic congener of morphine congener: a thing or person of the same kind or category as another.
Oxycodone formulations
As an SAO, it is available in IR preparations Single Agent: (oxycodone, OxyIR, or Roxicodone) Compounded with acetaminophen: (Percocet, Endocet, or Roxicet) or aspirin (Percodan or Endodan) SR version: (OxyContin)
SR oxycodone possesses many of the characteristics of an ideal opioid including
no ceiling dose, minimal side effects, absence or minimal active metabolite, easy titration, rapid onset of action, short half-life, long duration of action, and predictable pharmacokinetics
In comparison to SR morphine, SR oxycodone
it has a prolonged pharmacokinetic profile, which theoretically allows it to be solely administered on an every 12-hr dosing schedule
Milligram-to-milligram, compare to morphine oxycodone
is more potent than morphine and has a shorter onset of analgesia with less plasma variation.
Side effect of morphine compared to oxycodone
oxycodone is associated with fewer side effects (hallucinations, pruritus, dizziness) than morphine
Oxycodone Metabolism
While it possesses some intrinsic analgesic properties via activation of the k-opioid receptors, oxycodone is predominantly a prodrug. It undergoes hepatic metabolism via the cytochrome P450 2D6 enzyme where it is converted into oxymorphone, an active metabolite with mu-opioid agonist properties, and noroxycodone, an inactive metabolite
Careful dose titration must be made in those concurrently taking medications with potential interaction with
…SSRIs, tricyclic antidepressants (TCAs), or neuroleptics.
Oxycodone excretion
because the kidneys excrete oxycodone, the dose should be adjusted in renal dysfunction
Oxymorphone
semi-synthetic opioid
Oxymorphone formulation
IV preparation(Numorphan) rectal suppository (Numorphan). Oral formulation (Opana Immediate-Release and Extended-Release)
Oxymorphone compared to Morphine
Oxymorphone is primarily a mu-opioid receptor agonist that has more affinity for the mu-opioid receptor than morphine and is 10 times as potent as morphine when given IV Oxymorphone’s affinity for the delta-opioid receptor is greater than morphine, with agonism decreasing tolerance as well as potentiating m-opioid receptor mediated analgesia. Unlike oxycodone, oxymorphone has little to no affinity for the k opioid receptor.
Oxymorphone compared to Morphine and Fentanyl
Like fentanyl, oxymorphone has less histamine release from mast cells than morphine and is more lipid soluble than morphine and oxycodone. Unlike fentanyl, oxymorphone does not redistribute into fat stores, but rather dissociates slowly from receptors in the central nervous system. The increase in lipophilicity leads to maximum plasma concentrations in 30 min, compared to 1.2 hr for morphine-IR
Oxymorphone’s bioavailability compared to morphine’s and oxycodone’s
well absorbed in the GI tract, oxymorphone’s bioavailability is only 10% due to extensive first-pass hepatic metabolism. Even though oxymorphone’s bioavailability is lower than morphine’s (30%) and oxycodone’s (50%), oxymorphone’s greater lipid solubility facilitates its ability to cross the blood-brain barrier to bind and may account for its rapid onset of analgesia.
The time to maximum plasma concentration and half lives of oxymorphone, morphine, and oxycodone
is shorter for oxymorphone IR (0.5 hr) compared to morphine IR (1.2 hr) and oxycodone IR (1.5 hr). The half-lives for the IR (7–9 hr) and ER (9–11 hr) formulations are approximately two times longer than oxycodone and morphine.
The oxymorphone onset of analgesia for the IR formulation occurs
The onset of analgesia for the IR formulation occurs in 30 to 60 min and follows linear pharmacokinetics, allowing for predictable dosing. For the ER formulation, steady-state occurs in three days with every 12-hr dosing
Oxymorphone metabolism and excretion
Oxymorphone is hepatically metabolized and renally excreted. It does require dosing adjustment for hepatic and renal impairment. For those with moderate to severe hepatic impairment, oxymorphone is contraindicated
Main Metabolite of Oxymorphone
Oxymorphone-3-glucorinide, has unknown activity and is produced in the liver via uridine diphosphate glucuronosyl transferase enzymes after reduction or conjugation with glucuronic acid. A secondary metabolite, 6-OH-oxymorphone, is formed by reduction by an unknown enzyme and possesses analgesic activity.
Oxymorphone with Food and Alcohol
Since taking this medication with food can greatly increase the maximum plasma concentration, it is advisable to avoid eating at least 1 hr prior to or 2 hr after taking this medication. Alcohol should be avoided, as it can produce an almost 300% increase in the plasma concentration.
Hydromorphone
hydrogenated ketone analogue of morphine that can be formed by N-demethylation of hydrocodon
Hydromorphone Formulation
It can be given via oral, IV, epidural, or intrathecal routes for perioperative and postoperative pain / management. As an oral medication, it is available in an IR formulation (hydromorphone or Dilaudid) and SR formulation (Exalgo), with the latter affording once-daily dosing for chronic pain management
Hydromorphone compared to Morphine
Like morphine, hydromorphone is hydrophilic, possesses strong mu-opioid receptor agonist activity, and has a similar duration of analgesic effect (3 to 4 hr). However, side effects of pruritis, sedation, and nausea and vomiting occur less frequently with hydromorphone.
Hydromorphone compared to Morphine potency
Depending on whether it is administered orally or intravenously, hydromorphone’s milligram-to-milligram potency is estimated to be four to seven times that of morphine, respectively
Hydromorphone onset
Onset of analgesic effect occurs within 30 min when administered orally and 5 min when administered IV. Peak analgesic effect of IV hydromorphone occurs within 8 to 20 min, most likely because its hydrophilicity impairs its ability to cross the blood-brain barrier
Hydromorphone hydrophilic properties
Although it is hydrophilic, it is 10 times as lipid soluble as morphine. This feature, plus its greater milligram-to-milligram potency than morphine, allows equianalgesic doses to be infused subcutaneously but in smaller volumes (10 or 20 mg/ml)
Hydromorphone metabolism and excretion
Hydromorphone undergoes hepatic biotransformation into its primary metabolite, hydromorphone-3-glucuronide (H3G), with both the parent compound and metabolite being renally excreted. Similar to morphine’s M3G metabolite, H3G is an active metabolite that lacks analgesic efficacy but possesses potent neuroexcitatory properties
Hydromorphone-3-Glucuronide (H3G)
H3G is produced in such small quantities, its effects are negligible except in cases of renal insufficiency where it may accumulate. In those with renal insufficiency hydromorphone is preferable to morphine
METHADONE
derivative merging of the words that describe its chemical structure, 6-dimethylamino- 4,4-diphenyl-3-heptanone.
Advantages of Methadone
analgesic medication: low cost (wholesale price is approximately 5%–7% that of the more expensive proprietary SROs), high bioavailability with absorption and activity within 30 min, multiple receptor affinities, and lack of known metabolites that produce neurotoxicity (e.g., sedation, confusion, hallucinations, and myoclonus). Methadone is well absorbed and has an oral bioavailability
Why did FDA to issue a manufacturer’s black box warning for methadone?
unpredictable bioavailability and high interindividual variability in steady-state serum levels, can make it a challenge to initiate and titrate, thereby increasing the potential for delayed methadone-related side effects. unintentional overdoses
Methadone formulation
available as a hydrochloride powder that can be reconstituted for oral, rectal, or IV administration.
Methadone structure makeup
It is lipophilic, basic (pKa 5 9.2), and usually exists as a racemic mixture of its two isomers, d-methadone (S-met) and 1-methadone (R-Met), both of which have separate modes of action. The d-isomer antagonizes the NMDA receptor and inhibits serotonin and norepinephrine reuptake, while the l-isomer (R-met) possesses the opioid receptor agonist properties
Methadone compared to Morphine
lower affinity than morphine for the mu-opioid receptor, which may explain why methadone may have fewer mu-opioid receptor-related side effects.
Methadone agonist, antagonist, or both?
an opioid receptor agonist, NMDA receptor antagonist
What account for methadone’s ability to counteract opioid induced tolerance and dependence?
methadone has a greater affinity than morphine for the delta-opioid receptor. While delta-opioid receptor activity is felt to be crucial to the development of morphine-induced tolerance and dependence, methadone’s delta -opioid receptor agonism leads to its desensitization.
Methadone’s lipophilicity most likely accounts for its
extensive tissue distribution slow elimination delayed clearance (mean 3.1 ml/min/kg) which provides the basis for once-daily dosing for methadone maintenance therapy, thereby preventing the onset of opioid withdrawal syndrome for 24 hr or more
The ability to use methadone for either opioid detoxification or analgesia can be explained by
methadone’s biphasic elimination phase. This provides the rationale for prescribing methadone every 24 hr for opioid maintenance therapy and every 6 to 12 hr for analgesia
The alpha-elimination phase (distribution phase)
which lasts 8 to 12 hr, equates to the period of analgesia that typically does not exceed 6 to 8 hr Consequently, initial dosing for analgesia may need to be frequent because steady-state kinetics is required for reaching the biphasic profile
The b-elimination phase (clearance)
which ranges from 30 to 60 hr, may be sufficient for preventing opioid withdrawal symptoms but is insufficient for providing analgesia
Methadone metabolism
Unlike other opioids whose breakdown products contribute to potential neurotoxicity, methadone has no known active metabolites. It undergoes hepatic metabolism, primarily N-demethylation, by the cytochrome P450 (CYP) family of enzymes. As a result, methadone has multiple potential drug interactions that can result from induction, inhibition, or substrate competition at several of the CYP enzymes
Patients who are also taking what drug will absorb more methadone?
Omeprazole (Prilosec)
Excretion of methadone
Renal excretion of unchanged methadone is insignificant. However, decreases in urinary pH can significantly increase methadone excretion. It does not accumulate in renal failure and does not appreciably filter during hemodialysis.
Explain the potential for overdose or withdrawal symptoms with Methadone
Variability in protein binding, excretion, and equianalgesic potency can further contribute to methadone’s potential instability by provoking either overdose or withdrawal symptoms.
Methadone formulation
Unlike the SROs, methadone tablets can be broken in half or chewed. Methadone is also available in an elixir formulation (1 mg/ml or 10 mg/ml), which is advantageous for those with a gastrostomy feeding tube
Methadone’s pharmacodynamic property as an LAO makes it beneficial for those with
Impaired GI absorption secondary to “short-gut syndrome” or “dumping syndrome."It is also ideal for those with renal impairment, as it does not accumulate in renal failure and is insignificantly removed during dialysis.
Most concerning side effect of methadone
risk of cardiotoxicity– proarrhythmic potential—prolongation of QTc interval resulting in torsade de pointes.
A normal QTc interval is ≤430 msec for men and ≤450 msec for women
QTc prolongation is defined as >450 msec for men and >470 msec for women
Concerning risk of cardiotoxicity, the guidelines suggest clinicians should
inform patients of methadone’s risk of pro-arrhythmia, look for cardiac disease history, obtain a baseline EKG followed by periodic monitoring of the QTc interval, and be aware of other factors or medications that might contribute to a QTc prolongation
American Academy of Pain Medicine and American Pain Society recommended that a safe starting dose of methadone in most opioid naive adults is
2.5 mg orally every 8 hr with subsequent dose increases no more frequently than weekly. opioid-tolerant patients generally should start at doses no higher than 30 to 40 mg per day,
BUPRENORPHINE
Buprenorphine is a Schedule III semisynthetic opioid that is a derivative of the morphine alkaloid thebaine. Used primarily as an alternative to methadone maintenance therapy,
Buprenorphine formulation
Buprenorphine is available in the sublingual form as Subutex and Suboxone. The main difference between these formulations is that the latter also contains the receptor antagonist naloxone.
Suboxone: ratio of buprenorphine to naloxone is generally 4:1
Buprenorphine limited spinal analgesia, dysphoria, and psychotomimetic effects are due to its agonist, antagonist, or both?
Buprenorphine has partial agonist activity at mu-opioid receptor and antagonist activity at kappa- and delta-opioid receptors.
Compared to opioids that have full mu-opioid receptor agonism, partial mu-opioid receptor agonism results in
A ceiling effect for respiratory depression and causes less euphoria, the latter creating less craving. The decrease in craving may also be associated with antagonism at the k-opioid receptor.
Buprenorphine partial agonist activity results in a ceiling dose with a bell-shaped dose-response curve, suggesting
that buprenophine analgesic efficacy is limited and paradoxically can result in antagonism at higher doses
Limited spinal analgesia, dysphoria, and psychotomimetic effects are due to Buprenorphine
antagonist effects at the k-receptor.
Buprenorphine also acts on opioid receptor like-1 (ORL-1) receptors that may contribute to
antihyperalgesia, but it may counteract its antinociceptive effects.
Buprenorphine compared to Morphine
Buprenorphine is highly lipophilic and is thought to be at least 30 to 40 times more potent than oral morphine. it has a slow onset of action (approximately 90 min) in the sublingual form and relatively long half-life (4 to 5 hr).
Buprenorphine prolonged duration of action due to
Its slow dissociation from the mu-opioid receptor which explain the once-daily dosing in opioid treatment programs. The slow dissociation from the mu-opioid receptor may also be why cessation of buprenorphine induces only mild withdrawal symptoms.
Buprenorphine exhibits high affinity for the mu-opioid receptor, which allows for
attainment of effective analgesia at low receptor occupancy rates
Why use a higher dose of a full mu-opioid receptor agonist if added to a patient’s existing buprenorphine regime?
Because buprenorphine high affinity for the mu-opioid receptor blocks other opioids from binding,
Introduction of buprenorphine to a patient already taking an alternate opioid may precipitate
opioid withdrawal
The high affinity for buprenorphine for the receptor means that naloxone
may not readily reverse any buprenorphine-induced respiratory depression. The respiratory stimulant Doxapram may be more appropriate in this setting
Bioavailability of Buprenorphine
Due to first-pass hepatic metabolism, the bioavailability of buprenorphine is approximately 10% to 15%. However, when taken sublingually it has 60% to 70% of the bioavailability of the intravenous route
Buprenorphine metabolism
Buprenorphine is hepatically metabolized primarily via the cytochrome P450 3A4 enzyme into nonactive and active metabolites. The nonactive metabolites (80% to 90%) are the result of glucoronidation, and the active metabolite (norbuprenorphine) results from N-dealkylation
Norbuprenorphine
Norbuprenorphine is more potent with regards to respiratory depression, use of buprenorphine needs to be closely monitored in patients with moderate to severe liver dysfunction or those who are on concomitant medications that may induce the CYP 3A4 enzyme
FENTANYL Formulation
IV, epidural, and intrathecal routes transdermal application for the management of chronic pain and transmucosal and buccal applications for the management of breakthrough cancer pain.
Why does fentanyl have limited spread along the neuraxis when administered in the epidural or intrathecal space
Because fentanyl is highly lipophilic
Fentanyl agonist, antagonist or both?
Fentanyl possesses predominantly mu-opioid receptor agonist properties and little affinity for the kappa- and delta-opioid receptors
Fentanyl compared to Morphine
Compared to morphine, it has an inherently faster onset of action and is 75 to 125 times as potent
Fentanyl metabolism
It is hepatically metabolized by CYP3A4 into the inactive metabolite, nor-fentanyl.
Transdermal fentanyl (Duragesic patch)
Recommended for use only in opioid tolerant patients with chronic or cancer pain based on several studies reporting a 20% incidence of hypoventilation when it was used in acute postoperative pain management
Duragesic patch consists of four layers:
(1) the polyester backing layer is impermeable to drug loss or moisture penetration;
(2) the drug reservoir contains fentanyl gelled with hydroxyethyl cellulose and ethanol, the latter of which enhances transdermal absorption of fentanyl;
(3) the rate-controlling membrane helps control the rate of drug absorption, whereby 50% of the absorption rate is controlled by the membrane and 50% by the inherent resistance of the skin
(4) the silicone adhesive layer keeps the patch in place when affixed to the skin.
The patch should be placed on the
upper body on a hairless (clipped, not shaved), flat surface of skin free of defects. Once applied to the skin, sustained levels of analgesia can be achieved via fentanyl’s continuous transdermal absorption
How long does the fentanyl patch last?
Transdermal fentanyl permits 3-day dosing with avoidance of the first-pass effect of the liver, where fentanyl is metabolized primarily by the cytochrome P450 family of enzymes.
Benefit of Transdermal fentanyl patch
Because transdermal fentanyl does not pass through the GI tract, it theoretically causes less constipation than oral opioids.
Transdermal fentanyl patch useful in patient with
an inability to tolerate oral medications secondary to chronic nausea and vomiting, in those with impaired GI absorption secondary to “short-gut syndrome” or “dumping syndrome,” and in those who are noncompliant with taking oral medications
When using Transdermal fentanyl patch how long does it take before therapeutic serum levels are achieved?
1 to 30 hr (mean value of 13 hr) before therapeutic serum levels are achieved.Therefore, during the first 12 hr patients should be prescribed an SAO or IV PCA to address breakthrough pain and to minimize withdrawal symptoms if rotation is from another opioid, especially since it takes 3 days before steady-state is achieved.
How long does it take before serum fentanyl concentrations drop by 50% after the patch is removed?
it takes at least 16 hr before serum fentanyl concentrations drop by 50% after the patch is removed, one would also expect a delay in resolution of analgesia or side effects on removing the patch
In regards to Transdermal fentanyl patch Patients should be advised to
Avoid submerging the patch in hot water, placing a heating pad over the patch, or placing the patch over broken skin, as all of these can influence the rate of drug absorption and attendant side effects
Most common side effects of the transdermal delivery system
(<1%) are adhesive related and include erythema, itching, and occasional pustule formation
Breakthrough pain
Peaks in 3 to 5 min, lasts an average of 30 min, and occurs 1 to 4 times per day
Rapid-Onset Opioids (ROOs)
Defined by an onset of analgesia of 15 min or less currently available are Fentanyl preparations (oral transmucosal fentanyl citrate [OTFC; brand name Actiq]; fentanyl buccal tablet [FBT; brand name Fentora]; fentanyl buccal soluble film [FBSF; brand name Onsolis]; and sublingual fentanyl orally disintegrating tablet [sublingual fentanyl ODT; brand name Abstral]), only OTFC, FBT, and FBSF are available in the US.
Oral transmucosal fentanyl citrate [OTFC]
OTFC has a rapid onset of analgesia (15 min), short duration of action, and serum half-life of 193 to 386 min.Compared to the IV route, it has 47% bioavailability. Rapid absorption occurs via the buccal mucosa combined with slower absorption via the GI tract for the amount swallowed. OTFC yields peak serum concentrations within 20 to 40 min of starting a 15-min application.
Advantages of FBT over OTFC include
Fentanyl Buccal Tablet : FBT
Oral Transmucosal Fentanyl Citrate : OTFC
Faster median time to maximum peak serum concentration (47 min vs 91 min), greater proportion of transmucosal dose (48% vs 22%), greater early systemic exposure of fentanyl, and lack of sugar (dental caries)
Fentanyl buccal soluble film (FBSL; brand name Onsolis)
Submucosal ROO. The bilayer delivery technology uses a dual-layer polymer film consisting of a mucoadhesive layer that contains the active drug and an inactive layer that facilitates unidirectional flow to prevent diffusion of drug into the oral cavity.
Sublingual ODT
Orally Disintegrating Tablet
It is the only sublingual fentanyl. The delivery mechanism consists of a rapidly disintegrating tablet combined with soluble carriers coated with mucoadhesive agents, which enables the quick dissolution of fentanyl to take advantage of the highly permeable sublingual mucosa
Oral transmucosal fentanyl citrate [OTFC]
Fentanyl buccal tablet [FBT]
Fentanyl buccal soluble film [FBSF]
Sublingual fentanyl orally disintegrating tablet [sublingual fentanyl ODT USE
All are approved only for breakthrough cancer pain and have the benefit of bypassing first-pass hepatic metabolism. Total daily amount of a fixed opioid regimen is unpredictable, patients taking OTFC, FBT, FBSF, or sublingual ODT should be advised to start at the lowest dose and titrate to effect
SUFENTANIL
Used primarily in the operative setting as an IV or neuraxial analgesic, sufentanil (Sufenta) is a thiamyl analogue of fentanyl
Fentanyl compared to sufentanil
Sufentanil has a rapid onset with short duration of effect sufentanil has a smaller volume of distribution, greater analgesic potency (IV, five to seven times; epidural or intrathecal, two to five times), shorter half-life (2.7 hr vs 3.1 to 7.9 hr), and more rapid onset of analgesia (IV, 1 to 3 min; epidural or intrathecal, 4 to 10 min) with a shorter duration of effect (IV, 20 to 45 min; epidural or intrathecal, 2 to 4hr)
Sufentanil metabolism
Like fentanyl, sufentanil is lipophilic, predominantly hepatically metabolized by the CYP3A4 isoenzyme
Sufentanil side effect
Sufentanil may also produce dose-related skeletal muscle rigidity.
ALFENTANIL
Use as an IV or neuraxial analgesic, alfentanil (Alfenta) is less lipophilic compared to fentanyl and sufentanil. Its lower lipid solubility means it has a smaller volume of distribution (<25% of that of fentanyl and sufentanil).
Alfentanil Elimination half life, Onset of action, duration of effect
Its short elimination half-life (70 to 111 min) and rapid onset of analgesia (IV, 1 to 2 min; epidural, 5 to 15 min) with a short duration of effect (IV, 10 to 15 min; epidural 4 to 8 hr), makes it ideal in an operative setting due to the lower probability of accumulation with repeated dosing or continuous infusion and its ease of rapid titration.
Alfentanil metabolism
Like fentanyl and sufentanil, alfentanil is extensively metabolized in the liver by the CYP3A4 isoenzyme.
REMIFENTANIL
The most potent mu-opioid receptor agonist of the opioids remifentanil (Ultiva) is administered IV for the induction and maintenance of anesthesia
Compare remifentanil to fentanyl, sufentanil, and alfentanil
More lipophilic than fentanyl, sufentanil, and alfentanil, remifentanil also has a larger volume of distribution, a more rapid distribution and metabolism, a shorter elimination half-life (3 to 10 min), and a more rapid analgesic onset (1 min) with shorter duration of effect (5 to 10 min)
Metabolism of Remifentanil
Unlike fentanyl, sufentanil, and alfentanil, remifentanil is not metabolized to any appreciable degree by the liver. Instead, its ester side-chain linkage subjects it to rapid degradation by tissue and plasma esterases into an inactive carboxylic acid metabolite that is renally excreted
Advantages and disadvantages of remifentanil
Brisk clearance and lack of accumulation with repeated dosing are advantageous features in an operative setting, but discontinuation of the infusion results in a rapid loss of analgesia.
Equianalgesic dosage table
Buprenorphine (IM/IV): 0.4
Butorphanol (IM/IV): 2.0
Codeine (IM/IV): 120
Codeine (PO): 200
Fentanyl (IM/IV): 0.1
Fentanyl (Transdermal): 0.2
Hydrocodone (PO): 30
Hydromorphone (IV/IM/SC): 1.5
Hydromorphone (PO): 7.5
Levorphanol (acute PO): 4.0
Levorphanol (chronic PO): 1.0
Meperidine (IV/IM/SC): 75
Meperidine (PO): 300
Methadone (acute IV): 5.0
Methadone (acute PO): 10
Morphine (IV/IM/SC): 10
Morphine (acute PO): 60
Morphine (chronic PO): 30
Nalbuphine (IV/IM/SC): 10
Oxycodone (PO): 20
Oxymorphone (IV/IM/SC): 1.0
Oxymorphone (PO): 10
Tapentadol (PO): 75-100
Methadone Chronic dosing
0-99 mg: 4:1 100-299 mg: 8:1 300-499 mg: 12:1 500-999 mg: 15:1 >1000 mg: 20:1
