Tag Archive: antagonist


Buprenorphine interactions

Although there is significant confusion in the literature, buprenorphine is most commonly classified as a (partial) mu agonist/kappa antagonist. There is consensus that in the relatively ‘low doses’ used in clinical pain management, (5-100 mcg per hour), buprenorphine behaves like a ‚full‘ mu agonist. The partial agonist/antagonist effects seem only to become relevant for analgesia in very high doses used to treat opioid addiction (8-32 mg per day).

In patients on ‘analgesic doses’ of buprenorphine (eg transdermal), one can continue to use opioid analgesics for breakthrough pain in the usual way with good effect. The partial agonist/antagonist effect on supplemental opioid analgesia is not a major clinical issue. Other alternatives include sublingual buprenorphine or tramadol.

When treating acute pain after major surgery or trauma in patients on ‘high dose’ sublingual buprenorphine for addiction, continue the buprenorphine, using maximal multimodal analgesia including ketamine and neural blockade, supplemented with opioid PCA (using higher bolus doses) and monitoring the patient closely for adverse effects. In our experience, many patients undergoing major emergency surgery seem to do well with continuation of high dose sublingual buprenorphine and PCA fentanyl or morphine in appropriate doses. Conversion to standard opioids is complicated and often unnescessary.

Methadone interactions

Because methadone ‘saturates’ CYP450 (3A4) at low plasma levels (low hepatic clearance) compared with other opioids, it’s very ’susceptible‘ to;

  • The effects of a 30-fold variation in CYP450 enzyme activity between patients (fast, medium or slow methadone metabolisers), thus explaining the wide range of t1/2 (5-150 hours) and in part, highly variable clinical responses to methadone loading.
  • ‘Plasma accumulation‘, as the dose or frequency increases (the ’saturated‘ CYP450 can’t ‚burn off‘ the excess methadone):
  • Complex interactions with many drugs that share CYP450 for metabolism, particularly anticonvulsants, antidepressants, anti-microbial and antiretrovirals.

When prescribing methadone, always think about drug interactions at CYP450. Interactions are complex, with either induction (eg. phenytoin, rifamycins) or suppression (eg. fluvoxamine, fluoroquinalones, macrolides) of enzyme activity affecting methadone clearance, sometimes resulting in either withdrawal or accumulation respectively.

Methadone is highly-bound to plasma acute phase reactants (a1-acid glycoprotein), with the free methadone concentration decreasing when the level of phase reactants is raised (the free methadone is ‘mopped up’) such as in cancer or sepsis, leading to reduced analgesia or in rare cases withdrawal.

There are also substantial risks of over-sedation when methadone is combined with benzodiazepines, alcohol or THC.

Methadone, prolongs the QT interval in a dose dependent fashion (usually in doses greater than 200 mg per day) with case reports of Torsades de Pointes and VT. Check an ECG before commencing methadone, keep doses low and consider potential interaction with other drugs and conditions that prolong the QT interval.

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We are all naturally dependent on opioids for our emotional health. Both narcotics and internally generated endorphins exert their action on the body by interacting with specific membrane receptor-proteins on our nerve cells.

The body produces three large pro-compounds: proenkephalin, prodynorphin, and pro-opiomelanocortin. Endorphins can further decompose to small fragments, oligomers, which are still active. Oligomers pass the blood-brain barrier more readily. Enzymatic degradation of small-chain endorphins is accomplished by dipeptidyl carboxypeptidase, enkephalinases, angiotensinases, and other enzymes. This limits their lifetime in the unbound state.

Opioid receptors presynaptically inhibit transmission of excitatory pathways. These pathways include acetylcholine, the catecholamines, serotonin, and substance P. Substance P is a neuropeptide active in neurons that mediate our sense of pain; antagonists of substance P are currently under investigation as clinical antidepressants. Endorphins are also involved in glucose regulation. Opioid receptors are functionally designated as mu, delta, kappa, etc. These categories can be further sub-classified by function or structure. Decoding the human genome has allowed the genetic switching-mechanisms that control the expression of each opioid receptor to be determined at the transcriptional and post-transcriptional level.

All classes of opioid receptor share key similarities. Opioid-driven inhibition of neuronal excitability is mediated by the activation of a variety of potassium channels in the plasma membrane. The disparate subjective and behavioural effects evoked by activation of the different categories of opioid receptor are typically not the outcome of different cellular responses, but reflect the different anatomical distributions of each receptor. Unlike kappa opioid receptors, however, both mu and delta opioid receptors internalise on exposure to agonists. Activation of any type of opioid receptor inhibits adenylate cyclase, resulting in a fall in intracellular cAMP and diminished action potential firing. This causes a reduced flow of nociceptive information to the brain. Conversely, opioid addicts undergoing withdrawal suffer elevated cAMP levels and enhanced protein kinase A activity, resulting in increased neurotransmitter release.

The opioid receptors all have a common general structure. They are characteristically G protein-linked receptors embedded in the plasma membrane of neurons. Once the receptors are bound, a portion of the G protein is activated, allowing it to diffuse within the plasma membrane. The G protein moves within the membrane until it reaches its target – either an enzyme or an ion channel. These targets normally alter protein phosphorylation and/or gene transcription. Whereas protein phosphorylation alters short-term neuronal activity, gene transcription acts over a longer timescale.

Two new classes of opioid neuropeptide have recently been identified. These are nociceptin and the endomorphins.

Nociceptin (also known as orphanin) was first identified in 1995. It is the endogenous ligand of the opioid receptor-like 1 receptor. Depending dosage and site, nociceptin has subjectively extremely nasty hyperalgesic effects. Nociceptin receptor antagonists are candidate antidepressants and analgesics.

Endomorphin1 and endomorphin2 are newly-discovered ligands with the highest affinity and selectivity for the mu opioid receptor of all the endogenous opioids. Critically, endomorphin1 increases dopamine efflux in the nucleus accumbens via mu-1 opioid receptors. In the absence of selective endogenous mu-opioid receptor agonists, our vulnerability to pain and suffering would be even worse. Several novel, peripherally administered endomorphin1 analogues are under investigation that are more resistant to enzymatic hydrolysis. They should offer new opportunities for euphoric well-being, enriched mental health and more effective pain-relief.

Morphine itself is produced naturally by the human body and brain, albeit in much lower concentrations than in the opium poppy Papaver somniferum. Morphine is synthesised in human neuroblastoma cells via a biosynthetic route similar to that of the opium poppy. It is also present in healthy neurons, where it undergoes Ca2+-dependent release suggestive of a neurotransmitter or neuromodulator role. But the physiological role of endogenous morphine is still obscure.

Opioidergic neurons are particularly concentrated in the ventral tegmental area. The VTA is an important nerve tract in the limbic system. The VTA passes messages to clusters of nerve cells in the nucleus accumbens and the frontal cortex. This forms the brain’s primary reward pathway, the mesolimbic dopamine system. Its neurons are called dopaminergic because dopamine is manufactured, transported down the length of the neuron, and packaged for release into the synapses.

GABA normally plays a braking role on the dopaminergic cells. Opioids and endogenous opioid neurotransmitters activate the presynaptic opioid receptors on GABA neurons. This inhibits the release of GABA in the ventral tegmental area. Inhibiting GABA allows the dopaminergic neurons to fire more vigorously. The release of extra dopamine in the nucleus accumbens is intensely pleasurable.

Both delta opioid agonists and inhibitors of enkephalin catabolism have anxiolytic and antidepressant activity. Kappa opioid receptor antagonists have antidepressant activity; the first orally active selective kappa receptor antagonist is the investigational drug JDC-2. Mu receptor activation is crucial to the rewarding, analgesic and addictive properties of opioids. Government researchers and pharmaceutical companies are searching for powerful analgesics that won’t make the user feel happy [„high“] too.

Mu-receptors are found mainly in the brainstem and the medial thalamus. There are two primary sub-types: mu-1 and mu-2. More than 100 polymorphisms have been identified in the human mu opioid peptide receptor gene. Stimulation of the mu-1 receptors is primarily responsible for the beautiful sense of euphoria, serenity and analgesia induced by a potent and selective mu opioid agonist. Receptor activation by mu opioid agonists increases cell firing in the ventral tegmental area. This triggers dopamine release in the nucleus accumbens by reducing GABA’s tonic inhibitory control of the dopaminergic neurons. By contrast, at the height of the opioid withdrawal syndrome, typical firing rates and burst firings of VTA-nucleus accumbens neurons are reduced to around 30% of normal. The withdrawal syndrome can be quickly remedied by the administration of a potent mu agonist such as morphine. Care is needed: stimulation of the mu-2 opioid receptors helps modulate respiratory depression. For obvious reasons, this is potentially dangerous. The endogenous ligands for the mu opioid receptors have recently been discovered. They are endomorphin-1 (Tyr-Pro-Trp-Phe-NH2, EM-1) and endomorphin-2 (Tyr-Pro-Phe-Phe-NH2, EM-2).

Unfortunately, we still lack clinically available opioids specific to the mu-1 receptor. Their advent will (potentially) be a tremendous boon to mental and physical health.

Achieving effective, durable, and safe pain relief, especially
in patients with chronic and/or severe pain conditions,
can be a clinical challenge. For many types of pain, prescription
opioids are among the most effective analgesics [Fine
and Portenoy 2004]. However, there could be concerns about the
development of opioid tolerance or adverse effects, and in some
cases opioids seem to worsen pain (eg, hyperalgesia) [Compton
2008; DuPen et al. 2007; Stein et al. 2003]. For certain difficult
conditions, such as fibromyalgia or neuropathies, opioids alone are
sometimes considered of limited effectiveness [Chou et al. 2009].
Healthcare providers interested in pain management must be
alert to new or novel approaches that help to overcome deficiencies
of opioids, such as treatment-limiting side effects, and as aids
in relieving difficult-to-treat pain conditions. In this regard, there is
a growing body of evidence suggesting potential benefits of opioid
antagonists.
Opioid antagonists — in particular, naloxone and naltrexone —
have been available and studied for decades as agents that displace
opioid molecules from their neuroreceptors, and block
opioids from attaching to and activating those receptors. Such
qualities can be of important benefit, as short-acting antagonists
like naloxone are used effectively to quickly reverse toxic effects of
opioid overmedication or overdose.
Laboratory research and clinical trials have demonstrated the
unexpected, paradoxical effects of opioid antagonists as adjuvants
for enhancing rather than attenuating analgesic effects of opioids
like morphine, oxycodone, and others. Further benefits of opioid
antagonists, as monotherapy, for better managing certain chronic
pain conditions also have been discovered.

OpioidAntagonistsForPain