Analgesic Pharmacology

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This image was adapted from

Pain has been defined by the International Association for the Study of Pain (IASP) as an unpleasant sensory and emotional experience associated with actual or potential tissue damage[1]. Types of pain range across a broad spectrum, from neuropathic to somatosensory. As such, the multifaceted symptoms of pain require a treatment approach capable of targeting such a vast array of symptoms in order to achieve effective relief. As such, painkillers, also known as analgesics, are faced with the responsibility of ameliorating a subjective symptom ranging a broad spectrum of intensities[1]. It is important to study analgesics because pain is one of the most common complaints when seeking medical help, and thus analgesics are frequently prescribed. Classical analgesics target opioid receptors and cyclooxygenases while co-analgesics target a specific subunit of voltage gated calcium channels, NMDA channels and noradrenaline transporters[2]. Combining analgesics that act on different mechanisms of pain perception offers synergistic advantages and can decrease the incidence of adverse side effects[3].

1. Non-steroidal anti-inflammatory drugs

Non-steroidal anti-inflammatory drugs (NSAIDs) evoke pain relief by inhibiting the enzyme cyclo-oxygenase (COX) that is present in the body in two isoforms: COX-1 and COX-2. Older NSAIDs were less specific COX blockers, and thus did not specialize on a particular isoform. However, more recently marketed medication is predominantly aimed at inhibiting the COX-2 isoform[4]. NSAIDs are the most commonly used analgesic drugs because their over the counter nature makes them very readily available. The most well known of these drugs are Asprin and ibuprofen (a.k.a Advil). Both these drugs evoke similar relief from pain but act via different inhibitory mechanisms as outlined in the following video:

How do pain relievers work? (Asprin vs. Ibuprofen)
An overview of the mechanism of action of the most commonly used pain relivers
with respect to the everyday sensation of pain.

Mechanism of NSAID COX inhibition
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NSAIDs seem to follow a multistep kinetic mechanism for COX inhibition. Inhibitors with a low k2/k−2 ratio are rapid and reversible.
Inhibitors with a high k2/k−2 ratio are slow and tightly binding.The plateau of maximal inhibition indicates the extent of reversibility of the
compound. Rapidly reversible inhibitors are unable to completelyinhibit COX activity, so their maximal inhibition plateaus at non-zero values.
In contrast, slowly reversible inhibitors can completely inhibit
COX activity[7]

NSAIDs are known to bind to COX isoforms via 4 types of interactions:

  1. covalent bonding as seen in the acetylation of Ser530 by aspirin
  2. competitive binding as seen in the case of ibuprofen
  3. weak and time-dependent binding as in the case of naproxen
  4. tight and time-dependent binding as in the case of indomethacin[5].

Sulfonamides are preferentially used in the synthesis of selective COX-2 inhibitors such as celecoxib and valdecoxib because they exert inhibitory effect on carbonic anhydrase which is the enzyme implicated in the deceased tissue pH associated with tissue inflammatory responses[6].

Naproxen is known to occasionally induce gastrointestinal toxicity which can induce nausea/vomiting, gastric ulcers and diarrhea[7]. Selective COX-2 inhibitors and ibuprofen have been associated with increased risk of vascular events such as myocardial infraction and stroke[8].

1.1. Acetaminophens

Acetaminophen, such as paracetamol (a.k.a Tylenol) has a proposed mechanism of action and analgesic potency similar to NSAIDs as it also selectively binds to COX-2. However, it is not classified as a traditional NSAID due to its weak anti-inflammatory properties. Acetaminophens have been shown in previous studies to be unable to reduce inflammation associated with rheumatoid arthritis. This is due to the high extracellular concentrations of arachadonic acid and peroxide, both of which weaken the effect and destabilize the interactions of acetaminophen. However, acetaminophen has been shown to be able to reduce tissue inflammation in humans after oral surgery[9].

2. Opioids

World Health Organization analgesic ladder (cancer pain)
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The WHO principles direct clinicians to progress up the ladder if pain persists despite
the treatment outlined on the current step. This image was adapted from the Scottish Intercollegiate
Guidelines Network from a clinical guideline entitled:
Control of pain in adults with cancer from

Opioids, such as morphine, are common analgesics which can also exert a psychoactive effect. Opioids bind to 7 transmembrane G-protein coupled receptors (GPCRs) which are found in the central and peripheral nervous system as well as the gastrointestinal tract. Currently, four types of opioid receptors have been identified:

  1. morphine opioid receptor (µOP)
  2. ketocyclazocine opioid receptor (κOP)
  3. deferens opioid receptor (δOP)
  4. nociceptin opioid receptor (NOP-R).

However, it is speculated that post-translational modifications, alternative mRNA splicing and varying distribution in target tissues result in a myriad of additional pharmacological phenotypes[10]. Opiate is a more specialized term for a subclass of opioids, that refers only to non-peptide synthetic morphine-like drugs[12].

Once an opioid bind to its receptor it causes the closing of voltage-gated calcium channels resulting in hyperpolarization from the subsequent opening of potassium channels. Hyperpolarization causes the inhibition of cyclic adenosine monophosphate (cAMP) production by inhibiting the enzyme adenylyl cyclase. G-protein coupled inwardly rectifying potassium channels (GIRKs) regulate neuronal resting potential by acting as the primary postsynaptic effectors of GPCR signaling (i.e afore mentioned potassium channels)[12]. Opioid-mediated analgesia is thought to be regulated by GIRKs expressed by nociceptive dorsal root ganglion neurons (DRGs) present in the peripheral and central nervous system which are home to µOP, κOP and δOP receptors[11].

Opioids can be categorized into four groups based on their chemical and structural properties:

  1. naturally occurring endogenously produced opioid peptides such as dynorphin and met-enkephalin
  2. opium alkaloids such as morphine purified from the poppy Papaver somniferum such as morphine
  3. semi-synthetic opioids which are modifications to the natural morphine structure such as diacetylmorphine (a.k.a heroin)
  4. synthetic derivatives with structure unrelated to morphine which itself is broken down into a subseries
    • Methadone series (e.g methadone and dextropropoxyphene)
    • Benzomorphan series (e.g pentazocine)
    • Thebaine derivatives (e.g etorphine and buprenorphine)[12]

Opioids have been known to cause a number of adverse side effects including nausea, vomiting, constipation, heavy sedation and itching. Moreover, opioids have been known to impair cognitive function by evoking confusion, hallucinations and delirium and have been found to be correlated with incidences of depression. The severity of the effects of opioids has resulting in them having the highest dropout rate of all analgesic drug therapies, and due to this many clinical practices offer concurrent mindfulness programs. Patients who seem to require opioid therapy are strictly warned in advance of the possible complications and yet many of them still begin but are unable to continue treatment for long periods of time[12].

2.1 Alpha-2 Adrenergic Agonists and Antagonists

The α2-adrenergic receptors (α2ARs) are part of the G-protein coupled receptor family. They have three distinct subtypes which all share similar signal transduction pathways: α2A, α2B and α2C. The α2C receptor is known to have an important analgesic function in the spinal cord. α2C-dependent agonists cause α2ARs to synergize with opioid receptors resulting in adrenergic antinociception. Adrenergic agonists inhibit the release of peptides from the spinal cord in order to inhibit nociception of dorsal root ganglion neurons (the same cell type involved in opioid-mediated analgesia)[13]. α2 adrenergic agonists have similar potency to opioids but over time can induce tolerance. Their side effects are as of yet not clearly understood[14].

Interestingly, ultra-low doses of α2 adrenergic antagonists have been shown to paradoxically enhance the α2 adrenergic agonist-mediated antinociceptive effect and to block the development of tolerance against agonist treatments. Current clinical therapy uses agonists and antagonists in conjunction with one another to yield sustained pain relief[14].

2.2 N-methyl-D-aspartate (NMDA) receptor targeting agents

NMDA antagonists, such as ketamine, are usually administered alongside opioids because of their synergistic effects since NMDA antagonists are able to block the course of resistance to continuous opioid exposure. Excessive doses of opioids can trigger NMDA pain pathways in the central nervous system leading to hyperalgesia, and as such NMDA anatagonists can inhibit or reverse this sensitivity. The combinatorial application induces equally potent plain relief with less opioid consumption which relieves the patient of some of the very severe side effects of opioids[19]. Furthermore, dextromethorphan is a non-competitive low affinity NMDA receptor antagonist with minimal side effects. Studies have found that preemptive oral dextromethorphan can reduce the need for opioids in post-operative pain. The rationale behind this is that post-operative pain can be decreased by preemptively blocking NMDA receptors in order to prevent hyperalgesia from the sensitization of the pain pathways in the central nervous system[20].

3. Antidepressants

Target pathways of antidepressant analgesics
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The classical understanding of antidepressant analgesia leans toward a reinforcement signal through the monoamine-
containing bulbospinal pathways. Recent incidences of pain relief from topically applied antidepressants implicate a peripheral
level of action, but this pathway requires further study. Likewise, supraspinal effects which have been hypothesized as well
to contribute to antidepressant derived analgesia are also under further investigation[21].

Initially antidepressants were thought to possess analgesic potential because of their ability to inhibit NMDA receptors and decrease PGE2 production (gene which contributes to central sensitization and sustained pain sensation)[1].

Antidepressants mainly function by reinforcing descending inhibitory pathways by increasing the amount of norepinephrine and serotonin in the synaptic cleft in both supraspinal and spinal levels. They have been shown to be effective in the control of persistent pain due to their sodium channel blocking properties. The analgesic effects of antidepressants are independent of their antidepressive effects, and as such their antidepressive outcomes will be present patients treated for pain even if they are not diagnosed with depression[1].

3.1 Tri-cyclic antidepressants

Much remains unknown to this day about the mechanism of analgesic action of tri-cyclic antidepressants (TCAs). However, studies have managed to rule out interactions with opioid receptors as a possible mechanism. It is known that TCAs can bind with high affinity to neurotransmitter receptors and can facilitate the uptake of monoamines. Serotonin, dopamine and norepinephrine are all monoamines and have dramatic effects on opiate analgesia, with serotonin’s effect being most potent[15]. Therefore, a serotonergic mechanism of action has been hypothesized for TCAs given that TCAs are nearly as potent as opioids in relieving pain[1][15]. As such, the most widely prescribed TCA is amitriptyline because it has the most potent analgesic effect of all antidepressants[1]. However, high doses of TCAs can result in cardiovascular toxicity because the sodium channel blockage they cause results in an increased in cardiac action potential and refractory period, consequently delaying atrioventricular conduction[16].

3.2 Selective Serotonin Reuptake Inhibitors

Selective serotonin reuptake inhibitors (SSRIs), such as fluoxetine, have much better tolerated side effects than TCAs but are inferior in analgesic effect. has been shown that the SSRI analgesic mechanism is not exclusively related to activation of or interaction with opioid receptors. Fluoxetine has been shown to potentiate the effects of morphine, even though it is known that the serotonergic pathways are one step ahead of the endopioidergic pathways meaning that is it unlikely that the serotonin descending system plays an important role in opioid analgesia. The best current hypothesis suggests that SSRI-mediated analgesia functions primarily via the modulation of the serotonergic pathway and indirectly via the opioidergic pathway[17]. SSRIs are better tolerated because of their lack of anticholinergic, antihistamininc, antiadrenergic and cardiac side effects. However, some cases report that SSRIs can sometimes cause syndrome of inappropriate antidiuretic hormone secretion (SIDAH) which can be severe and occasionally fatal[1].

4. Gabapentanoids

Gabapentanoids, such as gabapentin and pregabalin originally entered the market as anitepileptics but were later found to have analgesic, anticonvulsant and anxiolytic effects. These drugs are becoming increasingly popular due to their tolerability from their lack of adverse side effects. Gabapentin specifically binds to the alpha-2 delta subunit of the presynaptic voltage gated calcium channels. This results in the inhibition of calcium release and subsequently prevents the release of excitatory neurotransmitters involved in pain pathways. Pregabalin is a structural analog of gamma-aminobutyric acid (GABA) and exerts its effect by binding to the alpha-2 lambda subunit of voltage gated calcium channels, which are expressed mainly in the brain and spinal cord. This leads to the inhibitory modulation of the release of several neurotransmitters resulting in neurons returning to a resting state from an excited state. Pregabalin has a unique ability to produce opioid-sparing effects (i.e reduce opioid requirements), prevent opioid tolerance and enhance the analgesic effect of opioids. Additionally, pregablin is more potent than gabapentin and has less associated adverse side effects, so pregabalin is clinically preferred to gabapentin[18].

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11. Nockeman, D., Rouault, M., Labuz, D., Hublitz, P., McKnelly, K., Reis, F. C., Stein, C. & Heppenstall, P. A. (2013). The K+ channel GIRK2 is both necessary and sufficient for peripheral opioid‐mediated analgesia. European Molecular Biology Organization: Molecular Medicine, 5(8), 1263-1277. doi:10.1002/emmm.201201980
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