The Management of Acute and Perioperative Pain Associated With Trauma and Surgery

Transduction

The conversion of signals of actual or impending tissue injury begins in the environment where the injury is taking place. It is believed that the primary sensory apparatus for the transduction of nociceptive signals is a network of free nerve endings that are capable of responding to a variety of signals, including mechanical (pressure), thermal, and chemical stimulation. These free nerve endings are believed to exist in most tissues throughout the body (the one notable exception being the brain itself) but are predominantly found in the skin. How various signals activate these nerve endings is poorly understood because studying these free nerve endings directly is very challenging. They are so small that they are difficult to locate and identify in vivo, let alone study. Histologically, it has been demonstrated that they are connected to Aδ- and C-type primary afferent fibers. Although it is not understood how various signals activate nociceptive nerve endings, it has been demonstrated that several biologically relevant chemicals either directly activate these nerve endings or sensitize them, prompting easier activation by other stimuli when they are present. Some of these chemicals, such as potassium, histamine, or serotonin, would be expected to be present in injured tissue, either released from the cytoplasm of damaged cells or from the bloodstream when nearby blood vessels are damaged. Others, such as bradykinins, prostaglandins, and leukotrienes, are synthesized by enzymes activated by tissue injury. Much like the skin, the nociceptive primary afferent fibers in muscle are now understood to respond to mechanical stimuli and chemical signals, but interestingly, muscle contraction itself can also generate signals in the nociceptors in muscle. One of the most potent stimuli that activate muscle nociceptors is muscle contraction under conditions of ischemia, believed to be transmitted by sympathetic nerves.

Transmission

Nociceptive signals are carried from the tissue in which they originate to the central nervous system by two types of primary afferent neurons ( Table 14.1 ): Aδ- and C-type fibers. Aδ fibers are large, lightly myelinated fibers that rapidly carry information about sharp, localized pain. C fibers are small, unmyelinated fibers that slowly carry information about dull, achy, throbbing, diffuse pain. Both of these fiber types originate from cells whose bodies are in the dorsal root ganglia. Anatomically, they are referred to as pseudounipolar cells. This type of neuron has an axon that divides but has no dendrites. The long, peripheral process generates the fibers discussed previously, and a shorter, central process enters the spinal cord and synapses with secondary afferent neurons in the dorsal horn of the spinal cord. Nociceptive signals are encoded in the firing pattern of these neurons, both in terms of frequency and pattern. Studies conducted in monkeys and humans have demonstrated that reported increases in pain intensity correlate with increased firing frequency in relevant sensory nerves, but this relationship is not linear or direct. It is possible to have pain in the absence of activity in nociceptive fibers, and it is possible to have activity in nociceptive fibers in the absence of pain. Situations like these most commonly occur after injuries to the nervous system, centrally, peripherally, or both, but they can also occur in normal individuals as a product of modulation, which is discussed later. Suffice it to say that the relationship between nociceptive input and pain is complex and variable.

Unlike pain arising from the skin, pain arising from deeper structures such as the viscera, and to a lesser extent, muscle and bone, is often dull, aching, and poorly localized, and it can often generate what is known as referred pain—that is, pain that is misperceived as originating from a site distant from the site of tissue injury. Referred pain can be a major source of confusion when examining a patient whose primary complaint is one of pain. Although it is widely recognized that visceral pain is often referred to somatic structures—for example, cardiac pain is often referred to the chest, back, left arm, and/or upper abdomen—it is far less widely understood that myofascial pain is also often referred and can generate the perception of pain in areas quite distant from the actual site of injury. This was demonstrated as early as the late 1930s by Kellgren. There are now clinically recognizable patterns of pain referred from specific muscles that have been well described, for example, by Travell and colleagues, both in the 1950s and in the 1980s.

There are four major physiologic mechanisms proposed to explain the phenomenon of referred pain: (1) activity in the sympathetic nervous system, (2) peripheral branching of primary afferent nociceptors, (3) convergence projection, and (4) convergence facilitation. Of these, the first two are mechanisms active in the peripheral nervous system, whereas the last two are central mechanisms.

A further explanation of these four major physiologic mechanisms is as follows:

• 1.

  Activity in the sympathetic nervous system may cause referred pain by producing and releasing substances in the area of referred pain that sensitize nociceptors or perhaps by altering blood supply to the sensory nerve fibers themselves.

• 2.

  Peripheral branching of nerve fibers to separate parts of the body may result in the brain misinterpreting signals originating in nerve endings in one area of the body as arising from nerve endings in the other area of the body.

• 3.

  The convergence-projection hypothesis states that because a single nerve cell in the spinal cord receives input from multiple primary nociceptive fibers that supply both visceral and somatic structures, the brain has difficulty distinguishing visceral input from somatic input. In such situations, the brain defaults to interpreting the input as coming from the somatic structures because they are much more commonly the source of such input.

• 4.

  The convergence-facilitation hypothesis states that the background activity of second-order pain-projection neurons in the spinal cord that receive input from one somatic region is amplified (facilitated) in the spinal cord by signals arising from nociceptors originating in another region of the body. Nociceptors producing the background activity originate in the region of perceived pain and tenderness; the nerve activity producing the facilitation originates elsewhere, for example, at a myofascial trigger point. This convergence-facilitation mechanism is of clinical interest because one would expect that blocking sensory input in the area of referred pain with cold or a local anesthetic (LA) should provide temporary pain relief. One would not expect such relief according to the convergence-projection theory. Both of these responses (the presence and the absence of temporary relief offered by blocking sensory input in the area of referred pain) have been demonstrated in clinical experiments.

Referred pain can pose serious problems for both patients and physicians when it goes unrecognized. Because the source of pain actually lies at a location distant from the perceived painful area, physical examination and diagnostic testing and imaging regularly fail to demonstrate any issue at the area perceived to be the source of the pain. This often leads physicians to believe that there is no physical reason for the patient to be experiencing pain and prompts both the physician and patient to suspect strong psychological components to the pain. This results in frustration on the part of the physician and ever-increasing anxiety on the part of the patient. Combined, these can lead to “doctor shopping,” no treatment, or inappropriate treatment.

Modulation

Modulation is a broad term used to describe the activity of a multitude of circuits and pathways throughout the central nervous system that ultimately terminate in the dorsal horn of the spinal cord. The earliest discovered of these systems functioned to decrease the transmission of nociceptive signals up the spinal cord to the brain. The concept of “spontaneous analgesia” was pioneered when Basbaum and Fields were exploring how electrical stimulation of specific brain regions could block typical responses to noxious stimuli in animal models. This phenomenon was termed “stimulation-produced analgesia” and quickly became a topic of serious interest when it was noted that stimulation of homologous regions of the human brain could provide relief for patients suffering from chronic pain. Electrical stimulation is not the only way to activate this pathway; opioids have been known to activate this same neuronal circuitry. Activation of this system by opioids is responsible for at least a portion of their analgesic effects.

One of the most important discoveries in the understanding of pain was the revelation that there are substances in the brain that mimic the pharmacologic activity of plant-derived opioids. These “endogenous opioids,” known as endorphins, enkephalins, and dynorphins, are found within neurons throughout the central and peripheral nervous systems. Particularly important is that they are concentrated in the brainstem regions previously known to be involved in spontaneous analgesia. The endogenous opioid system can be activated by a variety of stressors, including pain. This system has been shown to be activated after surgery and can have a significant analgesic effect. There are thus systems built into humans whose purpose is to provide analgesia, and these systems, like all biologic systems, show a large degree of interindividual variability. The variability in the activity of the endogenous opioid system and personality differences well explain why different patients undergoing the same operation can have such differences in their postsurgical pain.

Activity taking place in the spinal cord for the modulation of noxious signals does not always serve to suppress pain. There are also important processes that, when triggered, can serve to increase the transmission of signals from afferent nociceptors. A phenomenon referred to as spinal cord wind-up is, in the context of orthopaedic practice, one of the more important of these processes (more about this in Chapter 15 ). Wind-up refers to the observation that activation of peripheral nociceptive fibers, in particular, C fibers, is stimulated at a frequency of approximately 1 Hz. In this situation, second-order neurons in the dorsal horn of the spinal cord become increasingly responsive to the repetitive stimulation incoming from C fibers. Physiologically, this represents the temporal summation of excitatory postsynaptic potentials in the second-order spinal neuron that is driven by near-constant activation of the slow-conducting C fibers. This can not only serve to increase perceived pain in the presence of unchanging stimulation but can also widen the receptive field of the involved spinal cord neurons, which will produce pain that appears to be spreading in the face of unchanging stimulation. Spinal cord modulation can also result in increased perception of pain through a process referred to as central sensitization, which is effectively an increase in the sensitivity of neurons in the dorsal horn of the spinal cord to input from nociceptive fibers originating in inflamed tissue. This central sensitization can be quite pronounced, likely evolved as a protective mechanism to limit further injury to an already injured body part, and may contribute to the evolution of chronic pain states. Typical changes observed in neurons undergoing central sensitization include increased responses to noxious stimulation of inflamed tissue, lowering of the activation threshold of spinal cord neurons with an initially high threshold, increased responsiveness to stimulation applied to noninflamed tissue surrounding the area of inflammation, and expansion of the receptive field of the involved spinal neurons. In particular, the enhanced responses to stimulation of noninflamed tissue near the area of inflammation indicates that the sensitivity of the spinal cord neurons is enhanced so that previously subthreshold input is sufficient to activate the neuron under inflammatory conditions. The sensitization of individual spinal cord neurons will lead to an increased percentage of neurons in a segment that respond to stimulation of an inflamed tissue. Thus the population of responsive neurons increases. Central sensitization can persist for weeks. It is important to keep in mind that tissue inflammation will not only lead to increased responsiveness of the chemosensitive nociceptive fibers in that tissue but will also lead to increased responsiveness of the spinal cord neurons with which the peripheral nociceptors synapse.

Perception

It appears that nociceptive information is further processed within the brain and integrated with other information, ultimately culminating in awareness and the subjective experience we call pain. In the amygdala, nociceptive information is processed and combined with, among other things, emotional and contextual information. It is from this interaction that we develop a sense of fear and/or anxiety linked to pain and that reciprocal relationships can develop between pain and affective disorders. Likewise, the hippocampus is involved in the development of avoidance behaviors in response to pain and anxiety-induced hyperalgesia. Connections with higher brain centers and the amygdala facilitate the development of “pain memory,” allowing associations to be made between painful experiences and environmental cues. The nucleus accumbens (NAcc) in the striatum is also a key player in the central processing of pain. The NAcc functions in probability assessment, reward, and reinforcement processing. It is critically involved in risk–benefit analysis and reward processing such that it is a key structure involved in the development of behaviors such as drug abuse. Opioids and stimulants induce changes in the activity of neurons in the striatum that are consistent with other rewarding behaviors, such as food and sex. Not surprisingly, there are important connections between the NAcc, the amygdala, and the cortex. In light of these connections, the NAcc functions like a gatekeeper, either suppressing or enhancing the perception of pain based in part on the assessment of a reward in any particular situation. In the cortex, it appears that the secondary somatosensory cortex is the dominant area for the summation of all the various input and processing areas for pain. It is likely here that perception truly occurs, in that this is the area where noxious stimuli are recognized as painful and intensity is coded, along with other discriminatory aspects of painful stimuli. Connections between the secondary somatosensory cortex and the limbic system are also vitally important for the emotional, motivational, and memory aspects of pain.

Opioids

The central and peripheral nervous systems are composed of neurons, which themselves are composed of cell bodies, which are responsible for neuronal activity. Each neuron has a number of dendrites, which are short fibers that receive signals from other neurons and transmit them to the cell body. Also attached to the neuron is an axon, a long fiber that transmits messages from the cell body to other dendrons and from there to other neurons. Axons are also present in other tissues such as muscles and transmit electrical signals to them as needed. Nerves communicate with one another by neurotransmission, which occurs by releasing chemical messengers that transmit the message across the spaces or synapses between cells. These chemicals are released by the proximal cells of the synapses and bind to the receptors in the distal cells in the synapses of the dendrites (Video 14.2).

There are different receptors that send messages to the brain when they are exposed to stimuli, including temperature, mechanical, pH, and so forth. Nociceptors detect stimuli that can cause tissue damage and are found in most locations, but they proliferate in the skin, the walls of organs, and deep within other tissues such as muscles, joint capsules, and joints. The electrical impulse transmitted to the brain by nociceptors is pain. The signal is first sent via a primary afferent neuron to the dorsal root ganglion of the spinal roots. There the electrical current caused by the impulse initiates a release of neurotransmitters that passes the pain signal from the primary afferent neuron to a secondary excitatory neuron in the spinal cord. There are several neurotransmitters involved in pain signaling, the major ones being glutamate and substance P. The message is then sent to various locations in the brain, where it is interpreted as pain.

The thalamus receives the signal and provides context to the message. The thalamus releases the pain message to the hypothalamus and limbic system, which in turn help us to learn from the pain and avoid the cause of the pain in the future. This can modify our emotions and behaviors regarding pain. Catastrophizing, which is outside the scope of this chapter but more thoroughly covered in Chapter 15 , is perhaps a good example of such a behavioral/emotional modification to pain.

Opioids influence the pain signal at multiple locations in this pathway. They work in the brain, the spinal cord, and in the periphery. In the brain, opioids have mood-altering effects, cause sedation, and can also decrease the emotional response to pain. Opioids block the signal from the primary nociceptor to the primary afferent neurons, then from the primary afferent neurons in the dorsal root ganglion to the secondary excitatory neurons.

Opioids also work on neurons that descend from the brainstem to the spinal cord that modulate pain signals. Those descending pathways have fibers that either amplify or inhibit pain signals being transmitted to the brain. Opioids depress the fibers that amplify the signal and enhance the fibers that inhibit the pain signal. There is evidence that opioids can work peripherally to increase activation of primary neurons and inhibit immune and inflammatory responses to noxious stimuli.

When the signal is passed from the primary neuron to the secondary neuron at the synaptic cleft, an influx of calcium ions causes the release of neurotransmitters into the synapse. These neurotransmitters flow across the synapse and then bind with receptors on the postsynaptic neuron. This initiates the chain of events within the secondary neuron that further propagates the pain signal to the brain. There are specific opioid receptors on both pre- and postsynaptic neurons. When an opioid compound binds to the opioid receptor on the presynaptic neuron, it decreases the amount of calcium ions that can enter the cell, ultimately decreasing the amount of excitatory neurotransmitters that are released into the synapse. Opioids binding to the postsynaptic opioid receptors, in turn, decrease the response to any of the neurotransmitters released from the presynaptic neuron, which results in fewer pain stimuli transmitted to the brain.

It has been known for hundreds of years that opium possesses analgesic effects. During the 1970s, however, it became apparent that humans and other animals have an analgesic mechanism through endogenous opioids that modulate pain signals. These endogenous opioids, collectively known as endorphins, include beta-endorphins, enkephalins, and dynorphins. The endorphins interact with the opioid receptors to varying degrees, but they all have the tetra-peptide sequence tyrosine-glycine-glycine-phenylalanine (tyr-gly gly phe) in common. Exogenous opioid drugs and medications bind to opioid receptors in the same way but with more powerful and varying consequences.

There are three types of opioid receptors: µ (mu) receptors, κ (kappa) receptors, and δ (delta) receptors. When mu receptors are activated by an opioid agonist like morphine, hydrocodone, or heroin, for example, they will all produce analgesia, but they all will come with side effects as well. Kappa receptor stimulation is associated with hallucinations and dysphoria and an overwhelming sense of dissatisfaction, anxiety, or restlessness. Delta- and mu-receptor agonism can cause respiratory depression because opioid stimulation of the midbrain suppresses the body's ability to appropriately detect carbon dioxide levels. Other side effects include sedation and somnolence, urinary retention, constipation, nausea and vomiting, dizziness, and itching, among others. One of the worst side effects of opioids is tolerance, which means higher and higher doses are required to achieve the same level of pain relief. The exact cellular mechanism for this is not known, although there are many plausible theories. This is the basic cause of opioid dependence and addiction.

Opioids can be classified according to their effect at opioid receptors. In this manner, opioids can be considered agonists, partial agonists, and antagonists. Agonists interact with a receptor to produce a maximal response from that receptor (analgesia after morphine administration is an example). Conversely, antagonists bind to receptors but produce no functional response while at the same time prevent an agonist from binding to that receptor (naloxone). Partial agonists bind to receptors but elicit only a partial functional response no matter the amount of drug administered (buprenorphine). In addition, opioids can be categorized according to the type of opioid receptor at which they produce their effects. Classically, there are considered to be three opioid receptors. These receptors are all G-protein-coupled receptors and were originally named mu (after morphine, its most commonly recognized exogenous ligand), delta (after the vas deferens, the tissue within which it was first isolated), and kappa (after the first ligand to act at this receptor, ketocyclazocine). In 1996 the International Union of Pharmacology renamed the receptors OP1 (the delta receptor), OP2 (the kappa receptor), and OP3 (the mu receptor). In 2000 this nomenclature was changed again to DOP, KOP, and MOP. Now, however, owing to the extensive literature previously using the Greek nomenclature for opioid receptors (δ, κ, and µ), the International Union of Pharmacology recommends using this classification and the DOP, KOP, and MOP classification of 2000 (δ = DOP; κ = KOP; and µ = MOP). There are currently four naturally occurring compounds (morphine, codeine, thebaine, and papaverine), four semisynthetic compounds (diamorphine [heroin], dihydromorphine, buprenorphine, and oxycodone), and at least seven synthetic compounds (meperidine [pethidine], fentanyl, methadone, alfentanil, remifentanil, carfentanil, and tapentadol; see Table 14.1 and Box 14.1 for trade and street names of opioids).

Although there is good evidence from clinical trials to suggest that opioids are effective at treating pain in the short and medium term, there is a lack of high-quality evidence supporting their use for chronic pain states, with a series of recent Cochrane reviews questioning the use of opioids in this setting. These reviews report weak evidence to support using opioids to manage long-term noncancer pain and show only a small to moderate benefit with opioid administration in osteoarthritis coupled with an increased frequency of adverse events. Similarly, the use of opioids in the management of low back pain is not supported by high-quality evidence, whereas opioids in neuropathic pain conditions is supported only by evidence for their use in the intermediate term.