9.4 Pain Relief

Placebos

One of the most perplexing aspects of pain treatment is the placebo effect—this is when pain is relieved just because someone thinks they are receiving treatment, even when the “treatment” does not actually have any biological action on its own. A placebo is, by definition, inactive, and yet produces analgesia, i.e., pain relief (Klinger et al., 2014, 2018; Wager and Atlas, 2015; Mundt et al., 2017; Schafer et al., 2018; Vase and Wartolowska, 2019). (See Chapter 14 Psychopharmacology). A placebo can take the form of a dummy tablet, nasal spray, sham surgical procedure, magnetic treatment, or topical cream. The fact that the most effective analgesic placebo manipulations are (1) the presence of sensory cues that have been associated with effective treatment or pain relief in the past and (2) the expectation of pain relief, suggests that placebo effects are tied to learned associations with previous pain relief.

A placebo analgesic effect can be elicited acutely in a very large percentage of individuals in both experimental and clinical contexts. In many ways, the effect of a placebo is very real. Placebo analgesia has been linked with activity in the prefrontal cortex, and endogenous opioid release in both the descending antinociceptive systems and forebrain structures. In addition, placebo-induced reduction of responses to noxious stimulation in regions of the anterior cingulate and insular cortex, thalamus, and spinal cord correlate with reported pain relief. Placebo analgesic effects have been consistently demonstrated for pain conditions, such as dental postoperative pain, post-thoracotomy pain, low back pain, IBS pain, chronic neuropathic pain, and experimental somatic pain caused by noxious heat, electric shock, intramuscular saline injections, and exercise under ischemic conditions. Proper estimation of the placebo effect during the treatment of pain should be carefully considered, due to ethical issues. And just because the placebo effect can provide genuine relief of pain temporarily, it should not be relied on as a clinical tool by itself.

Over-the-counter treatments, physical therapy, and massage

The easiest and most common starting point to treat pain is over-the-counter (OTC) drugs, which mostly work by reducing inflammation. Aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) like ibuprofen (Motrin), and acetaminophen (Tylenol) work by blocking the production of inflammatory molecules, which in turn reduces pain, inflammation, and fever. While the inflammatory response is critical to fighting pathogens and stimulating tissue healing (see Chapter 17 Neuroimmunology), it can also go overboard, lasting too long (chronic pain) or being too intense (excessively high fever). Anti-inflammatory NSAIDS can therefore be an effective and beneficial tool that reduces pain while facilitating recovery. Physical therapy and massage (e.g., physical manipulation of the area, ultrasound therapy, thermal therapy, dry needling, etc.) can work by relaxing and/or strengthening muscles that modulate sources of pain. In addition, traditional Chinese acupuncture is an alternative option. It involves the insertion of extremely fine needles into the skin at specific "acupoints." This may relieve pain by releasing endorphins, or through activation of the Gate Control theory.

Opioids and endorphins

The use of opium as a drug dates back thousands of years BC. Morphine is one of the oldest drugs known and has become the “gold standard” analgesic to which all others are compared. Opioids produce their analgesic effects by binding to their three main (or “classic”) opiate receptors—mu, delta, and kappa–as well as one more recently identified ORL1 receptor. These receptors are located at a number of sites within the central nervous system, including the spinal cord and several specific supraspinal structures (Corder et al., 2018; Bagley and Ingram, 2020). These receptors do not exist to respond to opioid drugs, of course. They evolved to respond to our own endogenous opioid-like neurotransmitters, endorphins. Endorphins (β-Endorphin, enkephalins, dynorphins, nociceptin/orphanin FQ) bind to mu, delta, kappa, and ORL1 receptors, respectively (see Chapter 3 Basic Neurochemistry). Table 9.2 reviews the major endogenous opioids and also introduces morphine and naloxone as major exogenous opiates. While morphine (the agonist) mainly binds to the mu receptor, naloxone (the mu receptor antagonist) blocks all three receptor sites. Naloxone is most commonly used to counteract opiate overdoses in emergency settings. It can restore breathing in someone who has slowed or stopped normal breathing due to excessive intake of opioids such as heroine, fentanyl, oxycodone (OxyContin®), hydrocodone (Vicodin®), codeine, and morphine. It does this by out-competing the ingested opioid to bind to receptors, stopping current receptor activation and preventing further activation while the body metabolizes the remaining ingested opioid.

All opioid receptors are activated through G protein-coupled receptor (GPCR) mechanisms (see Chapter 3 Basic Neurochemistry). Via GPCRs, opioids inhibit voltage-dependent calcium channels or activate inwardly rectifying potassium channels, thereby decreasing neuronal excitability. Opioids also inhibit the cyclic adenosine monophosphate pathway and activate mitogen-activated protein kinase cascades, both activities affecting cytoplasmic events and transcriptional activity of the cell.

Figure 9.20 summarizes the changes at the level of nociceptor neurons and the spinal cord due to opiate exposure. The left side of the image shows normal sensory input from a nociceptor neuron to a spinal projection neuron. The right side shows the changes that occur in both the nociceptor neuron primary afferent and projection neuron with opiates present. Opiates like morphine or endorphin can bind to the mu receptors in the presynaptic terminals of the primary afferents, or to spinal cord projection neurons. Binding to the presynaptic terminals elicits presynaptic inhibition, leading to reduced neurotransmitter release (e.g., glutamate or SP); on the other hand, binding to projection neurons will directly inhibit their activity. Both presynaptic and postsynaptic inhibition contribute to spinal analgesia.

Figure 9.20 Opioid receptor mechanism in the spinal cord

Opiates also have effects at supraspinal sites such as the thalamus, the amygdala, and the sensory cortex. Opiate activity in these areas are likely to play key roles in the overall analgesic state. The midbrain and brainstem structures (i.e., the periaqueductal gray [PAG] and the rostroventral medulla [RVM]) are particularly important central regions where opioids act. We first learned about these regions as part of the descending inhibition pathways for pain (Figure 9.16). Figure 9.21 shows how direct injection of morphine into either of these sites causes antinociception (pain relief) via increased activity in the descending inhibitory effect on the dorsal horn of the spinal cord.

Figure 9.21 Central analgesia targets

Cannabinoids

Marijuana is from a plant called hemp. Its main, active ingredient is THC (short for delta-9-tetrahydrocannabinol). THC is active in modulating pain because it interacts with our endogenous cannabinoid (endocannabinoid) system. The most commonly studied endocannabinoid systems include anandamide, and 2-arachidonylglycerol (2-AG). Both anandamide and 2-AG bind to receptors (cannabinoid receptor-1, and -2 (CB1-R, CB2-R)) found throughout the body and nervous system. CB1-Rs are mainly in the brain, particularly in the substantia nigra, the basal ganglia, limbic system, hippocampus, and cerebellum, but are also expressed in the peripheral nervous system. Figure 9.22 shows an example of CB1-R distribution in the human brain. CB2-Rs are mostly expressed in immune cells, the spleen and the gastrointestinal system, and to some extent in the brain and peripheral nervous system.

Figure 9.22 Cannabinoid receptor distribution Binding of CB1 receptor averaged over 35 men shows high binding in many brain regions, including basal ganglia and cingulate gyrus. Image credit: Kantonen, T., Karjalainen, T., Pekkarinen, L. et al. Cerebral μ-opioid and CB1 receptor systems have distinct roles in human feeding behavior. Transl Psychiatry 11, 442 (2021). https://doi.org/10.1038/s41398-021-01559-5. CC BY 4.0

CB1-R modulates pain signaling in several regions in the peripheral and central nervous system, including the primary afferent terminals, the dorsal root ganglion (DRG), the dorsal horn of the spinal cord, the periaqueductal gray matter, the ventral posterolateral thalamus, and cortical regions associated with central pain processing, including the anterior cingulate cortex, amygdala and prefrontal cortex (Hill et al., 2017). Figure 9.23 shows how CB receptor activation inhibits presynaptic release, a reminder of processes we learned about in Chapter 3 Basic Neurochemistry. Through activation of the G-protein mechanism, CB1-Rs modulate the activity of a number of ion channels via inhibiting presynaptic voltage-dependent Ca²⁺ channels to reduce synaptic vesicle release, and also opening inwardly rectifying K⁺ channels to hyperpolarize the presynaptic terminal.

Figure 9.23 Function of endocannabinoid receptors

The net consequence of the CB1-R is therefore to augment membrane hyperpolarization and inhibit the release of neurotransmitters in several central and peripheral regions responsible for mediating pain signals. Exogenous cannabinoids, such as the THC in marijuana, can tap into this endogenous pain modulation network by activating CB receptors in the brain, spinal cord, and peripheral sites. For example, cannabinoid-induced analgesia has been demonstrated for both neuropathic pain and cancer pain (Atakan, 2012; Whiting et al., 2015; Stockings et al., 2018; Lossignol, 2019; Bouchet and Ingram, 2020; Finn et al., 2021).

Capsaicin

Capsaicin is the main active ingredient of the hot chili pepper. We first introduced the capsaicin receptor when we learned about its role in activating temperature sensitive TRP channels. TRP channels belong to a superfamily of 28 cation permeable channels and each one is sensitive to a specific range of temperatures (Samanta et al., 2018). Many of them also activate in response to specific chemicals. In 2021, a Nobel prize was awarded to the scientist who discovered a TRP channel that specifically responded to capsaicin (Caterina et al., 1997) (see Figure 9.7). This transient receptor potential vanilloid type 1 (TRPV1, formerly VR1) receptor is also activated by heat and protons (lower pH or acidic). It is located in both peripheral and central nervous systems. In the PNS, it is mainly presented in the C-fibers and Aδ fibers.

TRPV1 channels are non-selective cation channels that are permeable to Ca²⁺, Na⁺, and K⁺, meaning they net depolarize a cell. Activation of enough TRPV1 channels can ultimately result in action potential generation, leading to nociception. Interestingly, although the sensation associated with capsaicin in the short term is pain, in the long term, repeatedly treated tissue can become desensitized to subsequent noxious stimuli. Excessive Ca²⁺ influx leads to excitotoxicity (literally death from too much excitation) that causes nerve degeneration and loss of pain sensation. It has been found that baby rats treated with capsaicin lose their nociceptive behavior after they grow up (Ruda et al., 2000; Peng et al., 2003). This property has been explored for analgesic purposes (try to find capzasin cream over the counter in any pharmacy). This is also why people can build up a tolerance to spicy foods by eating them repeatedly.

Surgical treatment

Surgical approaches to treating pain fall within four broad classes: decompression, reconstruction, ablation, and modulation.

Decompression procedures are commonly performed to release entrapped sensory structures and potentially relieve pain. For example, carpal tunnel for the median nerve and fibular head for the common peroneal nerve is the most common place where the nerve can be compressed leading to pain. Cutting the carpal tunnel ligament can release the compression of the median nerve, which in turn, relieves pain.

Reconstruction refers to attempts to directly repair injured neural elements, such as the nerve grafting following peripheral nerve transection or nerve root replantation following brachial plexus avulsion (a tear of the nerve roots from the cervical segments due to extensive lateral bending of the head or pull of arm).

Ablation procedures aim to disrupt or transect the pain-signaling pathways in the periphery (e.g., peripheral neurectomy, dorsal rhizotomy, dorsal root ganglionectomy), spinal cord (e.g., anterolateral cordotomy, to cut the anterior lateral part of the spinal cord), brainstem, or pain-processing centers in the diencephalon and telencephalon. Cingulotomy (disconnecting the cingulate cortex from the rest of the brain) is a CNS ablation technique that evolved from frontal lobotomy (chop off a part of a lobe) that was developed to avoid the neurocognitive complications of lobotomy. The anterior cingulate cortex is a structure that has been implicated in contributing to the emotional aspects of pain. However, caution should be taken since bilateral cingulotomy for chronic pain showed side effects of worse executive function, attention, and self-initiated behavior, though language, motor control, and memory were not affected.

Modulation aims to alter pain signaling or processing either electrically (nerve stimulators) or pharmacologically (intrathecal drug pumps). The next section discusses stimulation-based pain relief in more detail.

Electrical/magnetic stimulation

Electrical stimulation of nerves, spinal cord, and/or brain can be used to relieve pain. Magnetic stimulation of the brain has also been successfully used to treat pain (Tan and Kuner, 2021).

Peripheral nerve stimulation can be used to relieve pain via both invasive and non-invasive methods. Transcutaneous electrical nerve stimulation, TENS, is a non-invasive method for stimulating the peripheral nerve. In TENS, electrodes on the skin transmit small electrical pulses to provide pain relief (Figure 9.24).

Figure 9.24 Transcutaneous electrical nerve stimulation for pain In transcutaneous electrical nerve stimulation, electrodes are placed on the skin and small electrical pulses are delivered to relieve pain. Image credit: By Wisser68, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=30217768)

Spinal cord stimulation (SCS) emerged as a direct clinical application of the gate control theory of Melzack and Wall published in 1965. It was designed to be effective in suppressing pain of a nociceptive nature (both acute and chronic), and has been in use since the early 1970s. It is now one of the mainstream treatments of neuropathic pain. This technique is based on the original idea that antidromic (against the action potential propagation direction) stimulation of the large fibers in the dorsal columns may activate the proposed gating mechanisms in the dorsal horn. It is also called dorsal column stimulation because of this focus on stimulating dorsal pathways. Figure 9.25 shows an example of this kind of electrode placement. The frequency is usually 60–100 Hz, and the pulse width is between 100 and 500 μsec. The effective amplitude varies but should be set to produce comfortable paresthesias, usually in the range of 2–6 V for "constant-voltage" systems (Sdrulla et al., 2018; Rock et al., 2019; Schmidt, 2019; Fontaine, 2021; Sun et al., 2021).

Figure 9.25 Spinal cord stimulation (SCS)

Motor cortex stimulation (MCS) has been found to be effective against some otherwise extremely therapy-resistant pain conditions: central post-stroke pain (as the consequence of damage of the thalamus by stroke) and trigeminal deafferentation pain (results from injury to the trigeminal nerve from trauma or surgery). Notably, central post-stroke pain is one of the most therapy-resistant neuropathic pain conditions, and MCS is one of the only treatments that have been shown to provide relief in this condition.

Intracerebral stimulation, or deep brain stimulation (DBS), is also useful for the management of pain otherwise resistant to any therapeutic modality. Two major target regions for stimulation are shown in Figure 9.26: (1) the sensory thalamic (STh) nuclei (ventral posterior medial [VPM], ventral posterior lateral [VPL]), and (2) the PAG/PVG region. There is solid evidence that stimulation in the sensory thalamus is selectively effective for neuropathic (deafferentation) pain whereas PAG/PVG stimulation appears to preferentially influence nociceptive or mixed forms of pain (Lefaucheur, 2017; Hussein et al., 2018; Senatus et al., 2020; Knotkova et al., 2021; Nüssel et al., 2021; Ramos-Fresnedo et al., 2022).

Figure 9.26 Deep brain stimulation for pain Two common sites for deep brain stimulation to relieve chronic pain are the sensory nuclei of the thalamus and the periaqueductal gray.

Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive and relatively painless tool that has been used to treat chronic pain, in addition to studying various cognitive functions with various neuropsychiatric disorders. It uses an electromagnetic coil to generate a magnetic field that passes easily and painlessly through the skull and into the brain (see Figure 9.27) (see Methods: rTMS). These pulses induce changes in cortical excitability at the stimulation site and transynaptically at distant areas to achieve its effect. It is found that rTMS is beneficial for treating neuropathic pain of various origins, such as central pain, pain from peripheral nerve disorders, fibromyalgia, and migraine (Gatzinsky et al., 2021; Zang et al., 2021).

Figure 9.27 Repetitive transcranial magnetic stimulation for pain In repetitive transcranial magnetic stimulation, an electromagnetic coil generates a magnetic field that changes electrical activity of cortical neurons. This can relieve chronic pain in some conditions.