• Opioids are natural or synthetic compounds derived from Papaversomniferum poppies.  
• Opioid agonists produce morphine-like effects (analgesia, euphoria, sedation, resp depression). 
  
• All drugs in this category bind to specific opioid receptors in the CNS and PNS to produce effects that mimic the endogenous opioids (endorphans, enkephalins, and dynorphins).

How Do We Pharmacologically Treat Pain?

Topical Analgesics:

Anticonvulsants/Antidepressants:

Opioids analgesics:

• Acute pain
• Chronic pain
• Pain flares

Opioids are typically not as effective for neuropathic pain unless given in combination with other analgesics (AEDs, antidepressant, NSAIDS)

Opioid Sites of Action for Analgesia:

• Opioid agonists activate the endogenous pain-suppressant neural system.
• Opioid agonists stimulate opioid receptors, whose endogenous activators are the opioid peptides, which serve as chemical messengers in the pain-suppressant neural system.

• Neurotransmitters in EPSNS:norepinephrine, serotonin, enkephalin, dynorphan, endorphans

• Multisynaptic pathway descends from somatosensory cortex to dorsal horn (DH).
• PAG: key modulator of pain transmissions w/ higher influences.
• Opoioid activation inhibits release of pain transmitters, stimulates endogenous opioid release, and causes excitation of inhibitory DH projection neurons.
• THE ENDOGENOUS PAIN SUPPRESSANT NEURAL SYSTEM:a multisynaptic pathway from the midbrain periacqueductal gray (PAG) descending to the dorsal horn of the spinal cord.  Neurons in the system use norepinephrine, serotonin and opioid neuropeptides as neurotransmitters. When activated, the pain suppressant neuronal system reduces pain perception by preventing release of nociceptive neurotransmitters and inhibiting projection neurons in dorsal horn of spinal cord.

• Drugs that enhance the action or prevent the degradation of NE and serotonin in CNS can have analgesic effects
• Opioids inhibit release of pain transmitters (Glutamate & Sub P) and inhibit firing ascending projection neurons pre- and post-synapticallyin DH.
• To better understand the diversity of actions of opioids, must understand the opioid receptor families.
• PHARMACOLOGICAL KEY CONCEPTS:  Drugs that enhance release or prevent degradation of norepinephrine and serotonin in the CNS (e.g., some antidepressants, amphetamine and related drugs) can produce analgesic effects, probably by increasing action of these transmitters in the Pain Suppressant Neural system. Some antidepressants are useful in some pain conditions.
• At the PAG,  Mu opiate actions block the release of GABA from tonically active interneurons causing an activation of PAG outflow,activation of forebrain and spinal monoamine receptors thatprovide sensory input to higher centers and mood. Stimulation of the PAG in the midbrain also activates enkephalin-releasing neurons that project to the raphe nuclei in the brainstem. 5-HT (serotonin) released from the raphe nuclei descends to the dorsal horn of the spinal cord where it forms excitatory connections with the "inhibitory interneurons" located in Laminae II.

• norepinephrine,
  
• serotonin, 
• enkephalin,
  
• dynorphan,
  
• endorphans

• G-protein coupled receptors
• mu receptors
  •Endogenous agonist:ß-endorphin;
  •morphine
  • analgesia, respiration, GI
  •Agonist-induced internalization
• delta receptors
  •Endogenous agonist: Met- and leu-enkephalin
  •analgesia, GI
  •Agonist-induced internalization
• kappa receptors
  •Endogenous agonist: dynorphin
  •analgesia, hallucinations
  •No agonist-induced internalization
• N/OFQ receptor: orphan receptor
  o high sequence homology
  o very low or no affinity for binding conventional opioid ligands
  orole in opioid physiology remains unclear.
• All coupled to inhibitory G-proteins which inhibit adenylyl cyclase (AC), increased K+ efflux, and reduced Ca2+ influx.

• psychotic like behavior (halucinations, dysphoria)

• Opioids decrease excitability by increasing K+conductances and decreasing neurotransmitter release: coupled to Gi/Go inhibitory proteins
• Mechanism Of Action = Inhibit adenylyl cyclase (AC), increased K+ efflux, and reduced Ca2+ influx.

   

• The mu, delta and kappa  receptors in endogenous neuronal settings are coupled, via pertussis toxin–sensitive G proteins, to inhibition of adenylyl cyclase activity, activation of receptor-linked K+ currents, and suppression of voltage-gated Ca2+ currents.

   

   

• TOP  PANEL:  Opioid agonists stimulate the 7-transmembrane G-protein-coupled µ-opioid receptor on the postsynaptic neuron (top panel). This initiates steps that reduce the release of neurotransmitters (e.g., glutamate, acetylcholine, norepinephrine, serotonin, substance P) and promote the efflux of potassium, which leads to hyperpolarization and hence reduced cellular excitability. In the central nervous system (top panel), these actions reduce the transmission of pain,

   

• LOWER PANEL:  In the gastrointestinal (GI) tract (lower panel), stimulation of μ-opioid receptors causes changes in gut motility and water secretion and absorption that may result in constipation and contribute to the development of postoperative ileus. In the GI tract, alvimopan blocks the binding of opioid agonists to the μ-opioid receptor and helps prevent constipation. Because alvimopan is largely unable to cross the blood-brain barrier, it does not block μ-opioid receptors in the central nervous system or interfere with centrally mediated opioid analgesia. Illustration by TainaLitwak, CMI.

   

• G-coupled inward rectifying Potassium channels (GIRK) channels are gated following the activation of GPCRs associated with pertussis toxin-sensitive G proteins (Gi/o) that directly gate the channel (blue). The phospholipid PIP2 is closely associated with the channel to stabilize its functional integrity.

   

• Opioid agonist drugs exert the same pharmacological effects in both the CNS & periphery, but differ in their pharmacokinetic properties.
• e.g., lipid solubility, latency to onset, duration of action, potency, ability to cross blood-brain-barrier, activity at different receptors, oral/parenteral potency ratio (e.g., oral availability), analgesic efficacy (none more efficacious than morphine).

Morphine

(8)

• Prototype Strong Opioid  Agonist for Moderate-Severe Pain
• Short duration of analgesic action(~ 4-6 hrduration)
  •m receptor agonist
  •Active metabolite: morphine-6-glucuronide
  •MS Contin ®: 12 -hrduration (controlled release)
  •Various oral and parenteral forms
  •Patient controlled analgesia (PCA)
  •Hydrophilic, so  can spread

- seen at both therapeutic and toxic doses. 

- most common cause of death in acute opioid overdose.

Pharmacological Actions of Morphine:

Continued

IMPORTANT DIAGNOSTIC ALLY:  Pinpoint pupil is important diagnostically because most other causes of coma and respiratory depression cause dilation of the pupil.

Pharmacological Actions of Morphine:

Continued (again)

• For moderate-severe pain 
• m opioid agonist 
• •Short duration of analgesic action ~ 4-6 hrduration
• •Used perioperatively & in patient-controlled post-op analgesia or to reduce coughing reflex
• •Oral and parenteral forms 
• •Highly lipophilic, so can stay localized

 (7)

• For moderate-severe pain 
• •m receptor agonist, highly lipophilic 
• •Short duration of analgesic action ~ 4-6 hrduration 
• •extremely potent (µg doses) 
• •widely used peri-operatively and for patient-controlled analgesia 
• •iv, intrathecal, epidural, transdermal, & transmucosalforms 
• •rapid onset and short lasting

• For moderate-severe pain
• Strong m receptor agonist, NMDA receptor antagonist
• Longer acting (t1/2 = 15-60 h), orally active
• Used post-op and in cancer pain
• maintenance Rx in opioid dependence
• Oral and parenteral forms
• Can induce Long QT Syndrome
• Methadone is difficult to use as an analgesic because of complicated pharmacokinetics, and differences in timing and duration of analgesia vs. respiratory depression, which can lead to accidental overdoses.

“Methadone is rarely, if ever, indicated for treatment of acute pain… and should only be prescribed by clinicians who are familiar with its risks and appropriate use and are prepared to conduct the necessary careful monitoring.”

Longer half-life results in slower development of tolerance and dependance

The additional mechanism of action (Nmda antagonist) also important for preventing tolerance

CLINICAL APPLICATION:

Detox of Heroin Addicts:  5-10 mg, po 2-3 times daily for 2-3 days… after d/c mild but endurable withdrawal syndrome.

Maintenance of Heroin recidivist, tolerance to 50-100 mg/day methadone is deliberately produced so that the addict experiences CROSS TOLERANCE to heroin (addiction-related reinforcing effects are reduced.)

Detox of Heroin Addicts:  5-10 mg, po 2-3 times daily for 2-3 days… after d/c mild but endurable withdrawal syndrome.

Maintenance of Heroin recidivist, tolerance to 50-100 mg/day methadone is deliberately produced so that the addict experiences CROSS TOLERANCE to heroin (addiction-related reinforcing effects are reduced.)

•  For moderate-severe pain

meperidine(Demerol ®)

(10)

•  For moderate-severe pain

No longer used as much

Levorphanol

(5)

•  For moderate-severe pain

codeine, hydrocodone*, tramadol

(10)

*prescribed most often

• THE MODERATE/INTERMEDIATE OPIOIDS ( for mild-moderate pain)
• Tramadol (ULTRAM) is a synthetic codeine analog that is a weak -opioid receptor agonist. Part of its analgesic effect is produced by inhibition of uptake of norepinephrine and serotonin. In the treatment of mild-to-moderate pain, tramadol is as effective as morphine or meperidine. However, for the treatment of severe or chronic pain, tramadol is less effective. Tramadol is as effective as meperidine in the treatment of labor pain and may cause less neonatal respiratory depression.

Heroin

(3)

Pentazocine

(7)

Buprenorphine

(6)

• a mixed partial agonist/antagonist
• Partial agonist at mu receptors; very weak antagonist activity
  •Very slow dissociation from mu receptor conveys long duration of action
  •Buprenex ®, post-op analgesic
  •Soboxone ® (with naloxone), for Rx of opioid abuse
• Opioids replaced and blocked by buprenorphine. – Buprenorphine competes with the full agonist opioids for the receptor. Since buprenorphine has a higher affinity (stronger binding ability) it expels existing opioids and blocks others from attaching. As a partial agonist, the buprenorphine has a limited opioid effect, enough to stop withdrawal but not enough to cause intense euphoria.

**Opioid’s Adverse Effects:

(12)

Important Drug Interactions with opioid analgesics

(6)

• Meperidine (Demerol®) and other long-acting narcotic analgesics are contraindicated with MAO inhibitors due to high incidence of hyperpyrexic coma
• Sedative Hypnotics & Sedating Antihistamines: Increased CNS depression, particularly respiratory depression, & enhanced analgesia 
• TCA’s, Antipsychotics:Increased sedation; variable effects on respiratory depression
• CNS depression is enhanced by other CNS depressants (ie., The depressant effects of morphine are enhanced by phenothiazines (neuroleptics), alcohol, benzodiazepines, monoamine oxidase inhibitors, and tricyclic antidepressants.)

   

• Meperidine (Demerol) + MAO inhibitor = hyperpyrexic coma

  Low doses of amphetamines enhance analgesia for unknown reasons.

• Hydroxyzine (antihistamine) also enhances analgesia.

THE OPIOID ANTAGONISTS

(6)

• Pharmacodynamics (no tolerance develops to antagonist effects)
• Single dose of naltrexone (100mg,po) will block injected heroin effects for up to 48 hours and decrease cravings.
• In absence of agonist, antagonists are inert
• In morphine treated patients, antagonist completely blocks effects in 1-3 minutes
• In OD patients, antagonists will normalize breathing, consciousness, pupil size and GI effects.
• In dependent patients (those chronically using and tolerant (ie, appear normal on opioids) antagonists will rapidly precipitate abstinence syndrome.

nalmefene  and naloxone  appeared to be efficacious, safe, and to yield similar clinical outcomes in double blind study of overdose patients

• Tolerance, loss of drug effect with chronic dosing. Couple of possibilties. Decoupling between gproteins and receptor. Or internalization of mu receptors

• less tolerence develops to mixed opioids, no tolerance to antagonists

Opioid Overdose

Treatment Strategy

• refers to opioid or narcotic pain relievers, including Vicodin(hydrocodone), OxyContin (oxycodone), Opana (oxymorphone), and methadone.

• Opiates can enhance dopamine release in central reward centers
• The rewards Circuits:  the mesolimbic DA projection from the ventral tegmental area (VTA) to the nucleus accumbens (NAc), and to a lesser extent on its afferent and efferent projection areas such as medial prefrontal cortex (mPFC), amygdala, and ventral pallidum

Certain groups are more likely to abuse or overdose on prescription painkillers.

Many more men than women die of overdoses from prescription painkillers.

Middle-aged adults have the highest prescription painkiller overdose rates.

People in rural counties are nearly twice as likely to overdose on prescription painkillers as people in big cities.

Whites and American Indian or Alaska Natives are more likely to overdose on prescription painkillers

About 1 in 10 American Indian or Alaska Natives aged 12 or older used prescription painkillers for nonmedical reasons in the past year, compared to 1 in 20 whites and 1 in 30 blacks.

“Inconsistent use of the terms addiction, dependence and tolerance often results in misunderstandings between regulators, health care providers, patients and the general public regarding the use of medications for the treatment of pain.”

“Because of this, pain is often undertreated and individuals stigmatized because of their use of opioids for medical purposes.” 

ortant Clinical Considerations

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In pregnant females use caution since (1) the opioids readily cross the placenta and (2) in neonates the BBB for opioids is effectively lacking. 

Opioids in near term or newborn animals can severely depress respiration.