Pathways to Discovery Blog

Why is post-operative pain under treated?

Adequate pain relief following surgical procedures is well-documented to improve the degree and time course of patient recovery. Nontheless, post-operative pain remains grossly under treated, with up to 70% of patients reporting moderate to severe pain following surgery (1). Perhaps the biggest underlying contributor to the under treatment of post-operative pain is simply a lack of information, both on the part of basic scientists as well as clinicians. Scientists are in the relatively early stages of investigation into the specific mechanisms contributing to the development of incisional pain, which may differ from those mediating acute pain induced by chemical or inflammatory algesic agents. Currently, clinicians essentially rely on treatments that have been developed for other painful conditions, most notably opioids, the side effects of which can hinder rehabilitation and recovery. 

Because opioids are the mainstay treatment for post-operative pain, as well as many other painful conditions, a lack of education regarding the incidence of side effects and abuse potential of this class of drugs can also contribute to under treatment. Proper use of adjuvants to opioid therapy and other currently available tretments is imperative for improving post-operative pain in the short-term. 

A better understanding of the mechanisms of post-operative pain will undoubtedly improve pain management following surgery and allow clinicians to better tailor treatment to individual patients and procedures. The development of novel alternatives to conventional opioid-based analgesia as well as new devices and delivery methods will be essential for improving post-operative pain relief.  

Current Treatments for Post-operative Pain

Opioid drugs such as morphine are widely used in the treatment of post-operative pain, particularly following major surgery. Although they are typically efficacious with regard to pain relief itself, the adverse side effects that accompany opioid administration often limit the utility of this class of drugs. As such, other treatments are often used in conjunction with opioid administration in order to achieve analgesia while reducing opioid treatments. For example chlonidine, an a2-adrenergic receptor agonist, sometimes accompanies fentanyl or other opioids given via epidural administration. In addition, opioids are typically more effective for treating pain occuring at rest rather than evoked pain caused by movement or coughing; therefore, combination therapy can also be useful for improving and hastening recovery and rehabilitation (3). This is an important aspect of post-operative pain treatment to consider, as severe pain and lack of mobility following surgery are risk factors for the development of chronic pain syndromes (4). 

Non-steroidal anti-inflamatory drugs (NSAIDs) are a second class of drugs that are typically given to patients following surgery. In fact, nearly all patients receive some kind of NSAID to treat post-operative pain (4). They may not provide sufficient pain relief on their own, especially after major surgery, but can be combined with opioids or other interventions to improve analgesia. 

Afferent neutral blockage, although not employed with particularly high frequency in the clinic, is an analgesic treatment that has gained more attention from preclinical researcher in recent years. One important benefit of local anasethetics, such as lidocaine, is that they are effective for treating mobilization-evoked pain and may improve long-term patient outcomes (4). In addition, this class of drugs is relatively safe and well tolerated. However, these drugs also have non-selective effects on neuronal transmission, so normal sensory perception is affected. In addition, there are some associated cardiac and neurological risks, especially with systemic delivery.

 

References:
1. Pyati, S. and Gan T.J. (2007) Perioperative pain management. CNS Drugs. 21(3):185 - 211.

2. Grinstein-Cohen, O. et al. (2009) Improvements and difficulties in postoperative pain management. Orthopaedic Nursing, 28(5):232-239

3. Brennan, T.J., et al. (2005) Mechanisms of incisional pain. Anesthesiology Clin N Am, 23:1-20

4. Breivik, H. and Stubhaug, A (2008) Management of Acute postoperative pain: still a long way to go! Pain. 137:233-234

 

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Pain Processing: Cation Channel Blockers. Choosing models of pain.

Sodium and calcium cation channel blockers.

There are several types of drugs that have been developed to decrease the firing rate of nociceptive neurons by blocking cation channels. Among the most commonly known are lidocaine and bupivacaine, typically used as local anesthetics, which form an intracellular block of the voltage gated sodium channels (VGSCs) that are necessary for action potential generation. Without action potential firing, nociceptors are unable to propagate their message, and pain is thereby blocked. The main disadvantage of this class of drugs is that without selectivity for nociceptive sensory neurons, tactile input is also lost, leading to the numbness that accompanies local anesthetic administration.

Sodium channel blockers are most commonly used to treat neuropathic and other types of chronic pain; as such, models of neuropathic pain, particularly peripheral neuropathy models, are an excellent option for testing novel compounds of this drug class. Their analgesic efficacy may be more widespread, however, as they have shown to be useful against inflammatory pain and in some post-operative pain models. Notably, they are also among the few drug types shown to be effective in models of visceral pain.

Voltage gated calcium channels (VGCC) are another pharmacological target for pain relief. Gabapentin and pregabalin fall under the classification of gabapentinoids, which, while structurally similar to the endogenous neurotransmitter GABA, do not function as such. Instead, they bind to the α2-δ subunit of VGCC to reduce calcium influx into nerve terminals and thereby decrease neurotransmitter release. The α2-δ subunit of VGCC is highly expressed in the dorsal horn of the spinal cord, and decreasing the release of glutamate and substance P from nociceptive primary afferent neurons here is likely the main mechanism of action for drugs of this type. However, disinhibition of endogenous descending inhibitory pathways at supraspinal sites may also contribute to their analgesic effects (1). Gabapentinoids are tested primarily in models of neuropathic pain, including both nerve injury and neuropathy models, which reflects their clinical utility. 

TRPV1 ligands

The development of more selective cation channel blockers as a solution to avoiding the side effects that accompany a general neuronal blockade has been the subject of much investigation recently. Transient receptor potential (TRP) channels are attractive targets, as they are predominantly expressed in nociceptive DRG neurons. Activation of TRP channels, therefore, has little or no effect on normal mechanical sensation, and drugs that target these channels could potentially avoid centrally-mediated side effects as well.

TRPV1 channels, in particular, are widely studied as a potential therapeutic target. TRPV1 is a non-selective cation channel is activated by capsaicin, the active ingredient in chili peppers, as well as heat. The function of TRPV1 is also modulated by a variety of sensitizing agents released after injury, including protons. Inflammation resulting from injury can reduce tissue pH, thereby activating TRPV1, causing an increase in sodium and calcium influx into the cell, and thereby contributing to the sensitization of nociceptors under these conditions (2). TRPV1 can be targeted through either antagonists to block activation directly or with agonists, which work by causing desensitization of the receptor following robust activation.

Given the effects of inflammation on TRPV1 function, it is not surprising that ligands for this receptor have shown efficacy in a variety of inflammatory pain models, including post-surgical and arthritic pain as well as standard inflammatory pain models (2). Similar to other cation channel blockers, they are also effective in models of neuropathic pain, particularly peripheral neuropathy models, and in some models of visceral pain.

Efficacy Models of Pain

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Whitepapers: Peripheral Nerve Injury models and Post-operative pain models

 

References:

1. Tanabe, M., et al., Pain relief by gabapentin and pregabalin via supraspinal mechanisms after peripheral nerve injury. J Neurosci Res, 2008. 86(15): p. 3258-64.

2. Patapoutian, A., S. Tate, and C.J. Woolf, Transient receptor potential channels: targeting pain at the source. Nat Rev Drug Discov, 2009. 8(1): p. 55-68 

Cannabinoid System as a target for pain relief.

The body's cannabinoid system consists of two cannabinoid receptors, CB1 and CB2, their endogenous ligands, which include 2-arachidonoyl glycerol (2-AG) and anandamide (AEA), and the enzymes that regulate the synthesis and degradation of these ligands. While the endogenous cannabinoid system serves naturally to modulate pain transmission, it can be exploited to provide more robust relief, either through administration of agonists at CB1 or CB2 receptors or through inhibition of degrading enzymes to increase endogenous cannabinoid levels.

CB1 receptors are expressed in neurons throughout the central and peripheral nervous system, including in the DRG, where noiciceptor cell bodies reside, the dorsal horn of the spinal cord, and the PAG, all of which are important sites for modulation of pain transmission. CB2 receptors, on the other hand, are not found in the CNS under normal conditions (although they may be upregulated in nociceptive neurons after injury) and are instead expressed in a variety immune cells and microglia. Although activation of either receptor can promote pain relief, CB1 receptors are responsible for the centrally-mediated psychomimetic side effects that sometimes accompany administration of cannabinoid receptor agonists such as tetrahydrocannabinol (THC).

Both CB1 and CB2 are GPCRs that signal predominantly through Gi/o to decrease VGCC conductance and activate GIRKs to hyperpolarize cells. Therefore, ligand binding to cannabinoid receptors results in decreased release of excitatory neurotransmitters from nociceptive neurons and post-synaptic cells exhibiting decreased excitability for signals they do receive. Activation of cannabinoid receptors on immune cells can similarly inhibit their function and thereby indirectly modulate pain processing. Since CB2 receptors are found primarily on immune cells and microglia, this indirect, anti-inflammatory effect is the primary mechanism by which CB2-selective agonists modulate pain responses.

Cannabinoid agonists have shown efficacy in acute models such as tail flick and capsaicin injection, as well as carrageenan and CFA inflammatory pain models. Translation from animal models to the human condition has been documented for a variety of neuropathic conditions as well as for post-operative pain relief; therefore, both neuropathic and post-operative pain models would be appropriate for testing novel compounds designed to target the cannabinoid system as well.

α2-adrenergic Agonists and Tricyclic Antidepressants Evaluating Compounds in Relevant Models of Pain

α2-adrenergic receptors (α2ARs) are found in many areas in throughout the nervous system, but the α2ARs on pre- and post-synaptic neurons in the dorsal horn of the spinal cord are the main target for both endogenous and exogenous analgesia. One of the major descending inhibitory pain pathways involves the projection of noradrenergic neurons in the locus ceruleus back down to the spinal cord to activate α2ARs at this site. These receptors can also be targeted pharmacologically through administration of selective agonists or through the inhibition of noradrenaline (also known as norepinephrine) reuptake by drugs such as tricyclic antidepressants.

α2ARs are divided into three subtypes, the α2A-, α2B- and α2C-ARs. All three are Gi/o coupled GPCRs. α2AARs are expressed mostly on the central, pre-synaptic terminals of nociceptors and inhibit VGCC on these terminals to reduce the release of excitatory neurotransmitters such as glutamate and substance P. At the same time, α2CARs, expressed primarily on the second order neurons in the dorsal horn, reduce excitability of these neurons by increasing conductance through GIRK channels [1].

Tricyclic antidepressants (TCAs) are used clinically for the treatment of various neuropathic pain conditions, including nerve injury and diabetic neuropathy. Importantly, their analgesic efficacy is independent of the co-existence of depression in patients. Most TCAs have some action on both serotonin and norepinephrine reuptake, but their analgesic actions are largely mediated by increasing spinal noradrenergic tone coming from descending pathways, which then increases activation of α2ARs to produce pain relief as described above.

In accordance with their clinical usage, animal models of neuropathic pain are widely used to test novel TCAs. In fact, TCAs show little efficacy in animal models of acute or inflammatory pain. Although neuropathic and other forms of chronic pain are common indications for the clinical use of α2AR agonists as well, they show robust antinociception in a much wider variety of animal models, including acute and inflammatory ones. Also, they are used both clinically for and in animal models of postoperative pain [1].

Reference

1. Pan, H.L., et al., Modulation of pain transmission by G-protein-coupled receptors. Pharmacol Ther, 2008. 117(1): p. 141-61.