Fiber
Primary function
Order of susceptibility
Signs of blockade
A-alpha
Motor—skeletal muscle
5th—last
Loss of motor function
A-beta
Sensory—touch, pressure
4th
Loss of sensation to touch, pressure
A-gamma
Proprioception
3rd
Loss of proprioception
A-delta
Fast pain, temperature
2nd
Pain relief, loss of temperature sensation
B
Preganglionic sympathetic
1st
Increased skin temperature
C
Slow pain, postganglionic sympathetic
2nd
Pain relief, loss of temperature sensation
Ascending Pathway
From the periphery, nociceptor activation initiates an action potential that then must ascend the nervous system to reach the brain (Fig. 24.1). This ascending pathway uses a 3-neuron model. A first-order neuron, or nociceptor, reaches the dorsal horn of the spinal cord, in the Rexed laminae, where it synapses with a second-order neuron. The cell body of this first-order neuron is in the dorsal root ganglion (DRG). The signal is then passed on to the second-order neuron, which then ascends the spinal cord to reach the thalamus, primarily via the spinothalamic tract. From there, a third-order neuron finally delivers this peripheral sensory information to the cortex of the brain, where pain is perceived.
Fig. 24.1
The pain pathway
The ascending process involves transduction, conduction, and transmission. Specifically, transduction is the process by which mechanical, thermal, or chemical energy is transformed into electrical energy. Conduction is the process by which this action potential travels through the nociceptor. This energy, via the process of transmission, will transfer information from the first-order to the second-order neuron and then further to arrive at the cortex. Finally, perception is the conscious experience of pain nociception, including sensory and emotional processes.
Descending Pathway
The descending pathway provides modulation of the perception of pain from higher centers. There is no discrete “pain center” in the brain. Descending pathways originate at the level of the cortex, the thalamus, and the brainstem. Activation of these descending inhibitory fibers can modulate or “block” the activity of laminae I, II, V, and VII dorsal horn neurons. Modulation is a complex phenomenon that changes the quality, severity, and duration of pain perception. The main neurotransmitters implicated are norepinephrine, serotonin, and the endogenous opioids. These impulses can work in an inhibitory or sometimes facilitative manner. Impairments in descending modulation may be responsible for the transition from acute to chronic pain.
These inhibitory systems can be activated by brain stimulation, peripheral nerve stimulation, and intra-cerebral microinjection of opioids. Centrally acting analgesic drugs can also cross the blood–brain barrier to activate these inhibitory control systems. However, it’s generally not this simple. Pain is a complex perception that is influenced by prior experience. This sensation is also influenced by emotional states. Hence, the response to pain management therapies varies from patient to patient.
Peripheral Modulation
A myriad of chemicals are released by injured cells, including hydrogen, potassium, prostaglandins, bradykinin, histamine, and cytokines such as interleukins and TNF-alpha. Substance P, glutamate, aspartate, and ATP have excitatory effects on nociception, while beta-endorphins, somatostatin, acetylcholine, enkephalins, glycine, GABA, norepinephrine, and serotonin have inhibitory effects on nociception. These chemicals serve several physiologic purposes, one of which is to sensitize peripheral nociceptors. The process, called peripheral sensitization, results in allodynia and hyperalgesia:
Hyperalgesia—increased response to what is usually a painful stimulus
Allodynia—painful response to what is ordinarily a non-pain stimulus
Peripheral sensitization in the acute stage can be protective, forcing organisms to learn behaviors that avoid further damage and protect the affected area. Persistant peripheral sensitization, however, contributes to the disease of pain.
Central Modulation
It was once believed that the brain had a finite number of neurons and degeneration with aging was an incessant process. However, subsequent research has shown how dynamic the adult human brain can be. In particular, pain can be a nidus of neural plasticity, thereby altering perceptions and thresholds over time.
The descending pathway can have both facilitative and inhibitory effects. Alterations in this pathway can lead to hyperalgesia, and in few cases insensitivity. Therefore, this is a source of interest as therapeutic changes to these systems may have profound consequences on pain perception as well as transition from acute to chronic pain.
Within the dorsal horn of the spinal cord, there are two subsets of neurons: nociceptive-specific (NS) and wide-dynamic range (WDR). WDR neurons lie in Rexed lamina III to V and respond in a graded fashion depending on the intensity of stimulus. Repeated stimulation of unmyelinated C-fibers at intervals of 0.5–1 Hz leads to not only increased discharges but expansion in receptor field size as well. This phenomenon, known as wind-up, is primarily attributed to C-fibers and the WDR neurons.
Clinically, pain wind-up is the perceived increase in pain intensity over time when a given painful stimulus is delivered repeatedly above a critical rate. Glutamate released by these pathologically sensitized fibers underlies this wind-up phenomena. Glutamate will interact with postsynaptic NMDA receptors, to further support the sensitization of the dorsal horn. Therefore, NMDA antagonism can be helpful in chronic pain patients who demonstrate this pain wind-up.
Similarly, chronic exposure to exogenous opioids can induce nociceptive sensitization leading to a state of opioid-induced hyperalgesia. This condition is characterized by a paradoxical response to opioid therapy, such that patients experience increased levels of pain with increasing doses. This should be suspected in patients with continued and progressing pain complaints despite escalating doses of opioids in the context of no further disease progression. Treatment strategies involve reduction of opioid therapy, and/or supplementation with NMDA receptor modulators.
The Gate Control Theory of Pain
As discussed above, the transmission of sensory inputs from primary first-order to secondary neurons is subject to modulation, or gating, in the substantia gelatinosa of the dorsal horn. Gating can provide anti-nociception via local segmental and/or widespread supraspinal pathways. Wall and Melzack’s Gate Control Theory (Fig. 24.2) proposes that pain is a functional balance between the ascending information traveling into the spinal cord via large and small nerve fibers, such that increasing activity of the large fibers can limit the transmission of information from smaller fibers. Thus, ascending non-painful sensory inputs (via large A-beta fibers) help gate the painful (activated smaller C-fibers) stimulus. Large fibers carry non-nociceptive information, whereas the small fibers carry nociceptive information. With a non-painful stimulus the large fibers are activated, which stimulate the inhibitory neuron. However, with a painful stimulus the small fibers are activated, which inhibit the inhibitory neuron causing the gate to open, which leads to pain.
Fig. 24.2
Gate control theory of pain (I inhibitory neuron, P projection neuron)
Types of Pain
There are different ways to describe pain. We have thus far discussed the ambiguity in describing pain by temporal relationships: acute versus chronic. Pain can also be described based on context such as related to iatrogenic treatment such as surgery, syndrome (post-herpetic neuralgia or trigeminal neuralgia), or cancer. Below are the commonly described types of pain based on mechanism. In an effort to standardize nosology, these are terms that should be utilized to improve communication among healthcare providers.
Nociceptive pain is physiological pain produced by noxious stimuli that occurs without tissue damage or sensitization (Table 24.2). In this model, a noxious stimulus is detected, but no physiologic change occurs to affect the nervous system. Nociceptive pain is further divided into somatic and visceral pain. Somatic pain is generally localizable and described as sharp. Visceral pain is non-localizable, diffuse, and aching pain. Structures that produce somatic pain include bones, tendons, and muscles. Visceral pain is associated with organs.
Table 24.2
Differences between nociceptive and neuropathic pain
Nociceptive
Neuropathic
Causes
Signaling from normal nerves detecting stimuli from damaged tissue, or potential damage to tissue if insult prolonged
Abnormal process of sensory input from damaged neural structures
Types
Somatic versus Visceral
Peripheral versus Central
Descriptors
Somatic: squeezing and sharp, dull and achy, easily located
Visceral: pressure-like, diffuse, squeezing, poorly localized
Burning, shooting, tingling, lancinating
Treatment
Responsive to opioids and non-opioids
Generally unresponsive to opioids, requiring use of adjuvants
Neuropathic pain is initiated or caused by a primary lesion or dysfunction in the central and/or peripheral nervous system. Neuropathic pain is commonly not reversible and often considered to be much more severe and resistant to treatment.
Functional pain is amplification of nociceptive signaling in the absence of either inflammation or neural lesions. Essentially it is pain that does not have any known organic cause, and is most often used to describe abdominal pain of unclear etiology.
Inflammatory pain is a result of tissue damage leading to inflammation which in turn leads to sensitization of the system. This leads to a physiologic change, which decreases the discriminatory ability of peripheral nociceptors as well as heightens sensitivity to all stimuli including spontaneous pain. These changes are usually temporary and part of the healing process. In small numbers of patients these changes are permanent and lead to chronic pain.
There are other types of pain that do not neatly fit into a category but deserve discussion.
Referred pain is pain that occurs in a non-damaged part of the body as a result of damage to another structure with shared neuronal pathways. A common example is Kehr’s sign. When a diaphragmatic injury occurs as a result of splenic injury, renal calculi, surgery, etc, patients can experience pain in their shoulders. This is because the phrenic nerve shares its cervical origin (C3–4) with the supraclavicular nerve.
Psychogenic pain is a psychiatric disorder that is manifested as pain. The DSM-IV attempts to group some of these disorders. Pain disorder is chronic pain that is a result of psychological stress. Somatoform disorder is symptoms that cannot be explained fully by a general medical condition, direct effect of a substance, or attributable to another mental disorder.
Acute Pain
The Joint Commission mandates that all patients have the right to adequate assessment and management of their pain. Better pain control, depending on the agents and modalities used, leads to benefits in terms of decreased cardiovascular and respiratory complications. Endocrine, immunologic, gastrointestinal, and hematological outcomes can be improved as well. Most importantly, quality of recovery is improved, as we are becoming aware that acute pain may in fact become persistent if not treated properly.
Hospitals have started employing Acute Pain Services to provide the best pain management for their patients. Complex large systems can compromise patient safety, requiring relentless communication and coordination with almost every specialty in medicine. Anesthesiologists board certified in Pain Management are in a unique position to lead a pain service, as they are intimately involved with surgical services in the operating room, understand that acute pain can become chronic, and have the skills to intervene. An acute pain service may also be linked to a chronic and/or palliative cancer pain service and, therefore, knowledge in dealing with these patients is equally important.
Pain Evaluation
The evaluation of pain requires a comprehensive and systematic approach to obtain a thorough history and physical examination to establish a differential diagnosis. Physicians must be meticulous diagnosticians to ensure treatable etiologies have not been overlooked. Secondary data including imaging, laboratory values and tests can aid in diagnosis. Additional assessment of the patient’s understanding of their pain, their goals, their psychosocial behavior, and their cultural beliefs is paramount for optimal pain management. There are several measures of pain which all attempt to objectify the subjective experience of pain. The Numerical Rating Scale (NRS), Faces Pain Scale (FPS), Visual Analog Scale (VAS), and the McGill Pain Questionnaire (MPQ) are the most commonly used in the United States.
When asking patients to rate the intensity of their pain, the appropriate scale for the appropriate patient and the appropriate situation should be utilized. The most frequently used is the NRS, which is a quick means to extract a morsel of information. Pediatric, elderly, or cognitively impaired patients may benefit from the Wong-Baker Faces Pain scale. Intubated patients may point on the VAS chart when able to follow commands.
Patient’s pain should be systematically assessed on a consistent basis. It is now commonly considered “the fifth vital sign.” The location and intensity of all the painful areas should be evaluated, while recognizing that perioperative pain may be related to factors other than post-incisional pain. Improper positioning and preexisting pain conditions commonly complicate the postoperative course.
The underlying mechanism or pain generator needs to be determined in order to provide the most focused therapy. Oftentimes, a specific cause cannot be determined. One of the best ways to define the etiology of pain is to have the patient use adjectives to describe the character of the pain (aching, burning, dull, electric-like, sharp, shooting, stabbing, tender, throbbing). Matching these descriptors to the likely type of pain can then tailor treatment.
In the postoperative period it is important to additionally determine the functional ability of the patient. Specifically does the pain affect the patient’s ability to deep breathe, cough, get out of bed, and ambulate while in the hospital? These functional benchmarks can prevent postoperative pulmonary complications such as atelectasis and pneumonia and hematological complications such as deep venous thrombosis and pulmonary embolism. Inadequate pain control is a common denominator.
Some providers use the PQRST (Provocation, Quality, Radiation, Severity, Timing) mnemonic that is used in first aid and will make variations for application to pain management. Additionally, electronic medical records can provide templates that practitioners can follow. Either way, a systematic approach to the pain assessment in each patient should be carried out regularly to ensure adequate pain management.
Analgesic Modalities Via Phases of Care
Understanding the phases of care in preventing and treating pain is important and challenging. The pre-anesthesia clinic plays a paramount role in understanding and stratifying patients who would be candidates for regional anesthesia and those that may require a higher level of acute pain management. Patients on opioids should understand that their tolerance to, and dependence on, opioids makes their postoperative care challenging. Often, fulfilling their chronic opioid requirements, not to mention providing additional analgesia for their acute pains, is a difficult task perioperatively. In some, the use of opioids is just not sufficient and may be counterproductive in those who develop opioid-induced hyperalgesia. These patients, in particular, will require a multimodal approach emphasizing non-opioid therapies.
Adjunctive medications such as gabapentin or acetaminophen can decrease pain and opioid requirements. Neuronal sodium-channel blockade with regional anesthetic techniques is one of the best ways to prevent and treat pain. Therefore, consider neuraxial as well as peripheral ways to employ regional anesthesia while appreciating the time and quality, the surgery, the contraindications, and the overall postoperative course.
During the intraoperative period, anesthesiologists are accustomed to identifying and treating pain. The goal is to ensure safe emergence with appropriate pain control using cardiovascular and ventilator measures to do so. It is in the post-anesthesia care unit or on the floor or intensive care unit that the Acute Pain Service first makes contact with the patient. Several things have or have not occurred to give the patient the proper pain management course up to that point.
Pain is subjective and the provider must accept the patient’s report of pain. Even when a patient states they have 13 out of 10 pain, recognize that it provides useful information. The patient’s level of pain and degree of pain relief should be assessed on a regular basis. It is important to follow trends and utilize whatever objective data are available. Of equal importance, the analgesic plan should be discussed with the patient and their family members—the hardest thing for family members is to see their loved one in pain, and to believe no one is doing anything about it. Therefore, it is important to understand the patient’s expectations for their pain management in order to offer reasonable goals of therapy while not compromising patient safety.
Preemptive Analgesia
Initiating an analgesic regimen before the onset of a noxious stimulus to limit the pain experience and prevent central sensitization is the concept of preemptive analgesia. The perioperative setting is where preemptive analgesic techniques are utilized most often as the exact timing and onset of the noxious stimulus are known and thus can be preempted. Allowing a barrage of nociceptive information to reach the spinal cord can be detrimental to the patient by altering both peripheral and central sensory processing. Thus, providing systemic mu-opioid agonists or local anesthetics via peripheral nerve or epidural catheters throughout the perioperative period are clinically effective ways of providing analgesia, blunting the pain response and avoiding central sensitization. Preemptive analgesia should be utilized for any activity, therapy, or procedure with the potential to activate A-delta and C-fibers.
Non-pharmacologic Measures
Extremes of temperature, whether hot or cold, can help to reduce muscle tension, or reduce inflammation. Acupuncture and electro-acupuncture have been shown to be of benefit in the acute setting both to improve pain and to reduce common side effects of opioid analgesics; however they require specific training and time to administer. Similarly, hypnosis has been shown to reduce pain associated with medical procedures but again is specialized and time-consuming. Transcutaneous Electrical Nerve Stimulation (TENS) has shown conflicting results in terms of an analgesic benefit in the acute setting, but it has been shown to reduce the need for pharmacologic therapies. Similarly, there is limited evidence of benefit in the acute setting for guided imagery. Nonetheless, these simple interventions should not be overlooked. Though the evidence to support their use is mixed, the risks are low and application of use is easy. For some patients, the benefits are significant.
Pharmacologic Measures
Acetaminophen
Acetaminophen, also known as paracetamol or APAP (acetyl-para–aminophenol), was synthesized in the late nineteenth century (Table 24.3). Its mechanism of action is speculated to be inhibition of a cyclooxygenase isotype, COX-3. It exerts its effect as both an analgesic and antipyretic. Although IV formulations have existed in the UK, Australia, New Zealand, Japan, and India for many years, the United States did not have FDA approval for IV acetaminophen until 2010.
Table 24.3
Commonly used non-opioid analgesics in adults
Drug | Usual dose (mg) | Maximum dose (mg) |
|---|---|---|
Acetaminophen | 650–1,000 q 6 h | 4,000 |
Ibuprofen | 400–800 q 4–6 h | 3,200 |
Diclofenac | 50, q 6–8 h | 200 |
Ketorolac | 15–30 q 6 h—IV | 120—IV |
Naproxen | 250–500 q 6–8 h | 1,500 |
Celecoxib | 100–200, q 12–24 h | 400 |
The major concern is hepatotoxicity, acute liver failure, and death. It is the number one reason for acute liver toxicity in the Western world. In adults, the limit is 4 g/day; however still, individuals are susceptible to liver damage. Other insults such as alcohol use and hepatitis contribute to the risk of liver damage when taken with APAP. Because APAP is an antipyretic, one must be aware that there are situations where the addition of APAP may prevent fevers from occurring, which are an early sign of an inflammatory response or infection.
COX Inhibitors/NSAIDs
These drugs have been ubiquitously called Nonsteroidal Anti-Inflammatory Drugs (NSAIDs). Drug nomenclature is evolving to describe drugs based on the mechanism of action if known; therefore, this author describes them as COX inhibitors. Understanding the arachidonic acid metabolism pathway and the relative COX-1 to COX-2 inhibition of drugs in this class can help direct therapy. These drugs have anti-inflammatory, antipyretic, and analgesic effects.
The COX-1 inhibitors are associated with renal, gastrointestinal, and hematologic toxicity. COX-2 inhibitors produce less GI toxicity; however they can increase cardiovascular risk over time. Therefore, if patient is without serious GI contraindications, dual COX agents (ibuprofen) are recommended with concomitant use of GI prophylaxis.
Despite the ubiquitous use of NSAIDs, adverse clinical syndromes (hypertension, salt and water retention, edema, hyperkalemia) are infrequent. Nevertheless, patient populations at risk for renal adverse effects, including those with age-related declines in glomerular filtration, hypovolemia, congestive heart failure, cirrhosis or nephrosis, and known preexisting renal insufficiency, should use other modalities.
Antiepileptic Drugs (AEDs)/Anticonvulsant Drugs (ACDs)/Membrane Stabilizers
Originally developed for seizure prophylaxis and treatment, neuronal channel blockers have a role in pain management. Medications from this class are most effective for neuropathic pain conditions (e.g., post-herpetic neuralgia, trigeminal neuralgia, phantom limb pain) or diseases that are known to cause neuropathy (e.g., diabetes, HIV, cancer, and its treatments). The most commonly used agents are gabapentin, pregabalin, lamotrigine, levetiracetam, carbamazepine, oxcarbazepine, tiagabine, topiramate, and zonisamide.
While these drugs are mostly utilized in chronic and cancer pain, there is growing interest in these medications in the acute pain setting. For example, gabapentin is being used preoperatively to help with postoperative analgesia. Interestingly, studies have shown that the anesthetic requirements are decreased with this premedication; however optimal dosing is still being investigated.
Benzodiazepines and Antispasmodic Drugs
In patients with unremitting pain, the descending inhibitory actions of GABA may be compromised such that pain signals are conducted unfiltered to the brain. Benzodiazepines, such as diazepam, have been shown to enhance the action of GABA to alleviate chronic pain when delivered into the spinal canal. In practice, however, such injections are done in a few selected cases. More often, benzodiazepines are administered orally or parentally for systemic uptake to act on GABAA receptors in the spinal cord. However, undesired consequences stem from additional actions on the brain—sedation, delirium, and memory impairments.
Baclofen is a derivative of GABA and is an agonist for the GABAB receptors. Beneficial antispasmodic effects result from actions at spinal and supraspinal levels. A beneficial property of baclofen is in the possible treatment of alcohol dependence by inhibiting withdrawal symptoms and cravings.
Other antispasmodics commonly used are carisoprodol, cyclobenzaprine, tizanidine, methocarbamol, and metaxalone. These drugs have the effect of causing muscle relaxation via disparate mechanisms. Each drug in this class behaves somewhat differently with different side effects. While typically muscle relaxant medications are not used in the acute setting, there are situations when they might be useful. Short-term use of cyclobenzaprine has been shown to be effective for acute pain symptoms.
Intravenous Local Anesthetics
Most studies of intravenous (IV) lidocaine have been conducted on patients with neuropathic pain syndromes. Cell membranes of injured peripheral nerves can exhibit an increased density of sodium channels which contribute to persistent non-evoked discharges that produce a central hyperexcitable state. Therefore, inhibition of sodium channels by lidocaine can inhibit neuronal ectopic discharges. Studies have shown that IV lidocaine infusions (1–6 mg/kg over 30–60 min) are clearly superior to placebo only in the first day of therapy, probably superior to placebo after 5 days, and no better than placebo after 1 week. There have been other studies demonstrating the benefit of lidocaine IV infusions in post-laparotomy analgesia.
Topical Agents
Topical ointments, gels, salves, and patches have been developed to provide analgesia. They are the oldest method of drug delivery. The general principle is that they work at the site of action without significant systemic absorption. Caution should be employed to avoid placing these patches over open wounds or areas of skin compromise. Additionally, patients with increased BMI may not have good tissue penetrability for the drug to provide benefit. Nearly every class or analgesic agent can be prepared by compounding pharmacies for directed topical use.
Lidocaine (5 %) can provide adequate sodium-channel blockade to the nerves that it contacts. It can be helpful for superficial neuropathic and musculoskeletal pain complaints. Capsaicin cream is derived from the extract of hot chili peppers. It works at the vanilloid receptor TRPV1 and its use depletes substance P and other neuropeptides causing analgesia; it is most widely used in neuropathic pain. Topical diclofenac can provide COX inhibition, which can be useful to attenuate inflammatory pain.
NMDA Antagonists
Compounds which antagonize the NMDA receptor include ketamine, dextromethorphan, nitrous oxide, and memantine. Thus far the one that is used most often in acute postsurgical pain is ketamine, although active research is under way on memantine. Ketamine, a dissociative hypnotic, can be used at low doses (high doses may produce hypersalivation, sympathomimetic, and psychogenic effects), while providing analgesia. It is clinically useful in patients with opioid tolerance because it mitigates opioid use and improves VAS scores. At low doses it has anti-hyperalgesic properties. Methadone and levorphanol are mu agonists with additional NMDA-antagonistic properties so should be considered for those on chronic opioid therapy with signs of wind-up or hyperalgesia.
Opioids
Opioids are the most ubiquitous and arguably most effective pharmacologic agents to provide analgesia (Table 24.4). The most accurate nomenclature states that all compounds that work at opioid receptors should be called opioids. The term narcotic is a legal term and should be reserved for those in law. Additionally, the term opiate should be reserved for naturally occurring alkaloids such as morphine, thebaine, or codeine. Some of the principles relevant to acute pain management include:
Table 24.4
Commonly used opioids in adults
Opioid | Oral dose (mg) | IV dose (mg) |
|---|---|---|
Morphine | 10–30 q 4 h | 4–10 q 2–4 h |
Morphine controlled release (MS Contin) | 15–30 q 8 h | – |
Hydromorphone (Dilaudid) | 2–4 q 4 h | 0.2–1 q 4 h |
Oxycodonea | 5–10 q 4 h | – |
Oxycontin (extended release oxycodone) | 10–20 q 12 h | – |
Tramadol | 50–100 q 4–6 h | – |
Codeine | 15–60 q 4 h | – |
Hydrocodoneb | 5–10 q 4 h | – |
Transdermal fentanyl (25 mcg/h)c | Every 3 days | – |
1.
Routes of administration
2.
Patient-controlled analgesia
3.
Managing side effects
4.
Opioid conversion
Routes of Administration
Opioids can be administered via almost any route of administration. Generally, the postoperative period is a time when patients must remain NPO and the preferred route of administration is intravenous. Intramuscular injection has fallen out of favor due to variability in kinetics and adverse reactions, but still has use in select situations.
Opioids that have (a) a short time of onset, (b) steady maintenance state, and (c) non-active metabolites are preferred in acute pain management. The naturally occurring alkaloid, morphine, is the father drug for opioid management. It is one of the essential drugs per the World Health Organization (WHO). However, it has its deficiencies: its onset of action can take 30 min, it can be histaminergic, and its metabolites, particularly morphine-3-glucuronide, can be neurotoxic. Hydromorphone, on the other hand, has a shorter onset of action, is less histaminergic, and its metabolites seem to be less active than morphine—therefore, is better tolerated in patients in renal failure. Fentanyl is a lipophilic medication that is often misnomered as a “short-acting drug.” True, its duration of action is related to its large volume of distribution, and therefore, it is redistributed quickly. However, the half-life of fentanyl is similar to morphine and hydromorphone, but only when it approaches its volume of distribution.
Sustained release formulations should generally only be initiated in the acute setting if pain is present most of the time, and it is assumed that the pain generator will last for an extended period of time (>2 weeks). Additionally, these long-acting formulations should be reserved for opioid-tolerant patients once it is clear that around-the-clock therapy is necessary. Opioid-naïve patients should be initially treated with immediate release versions to ensure tolerability, prior to transition to sustained release agents.
Although formulations of transdermal, transmucosal, transbuccal, and intranasal opioids have been created, there are inherent issues with safety that prevent their use in the acute postoperative setting. However, there are select cases when such routes can be utilized. Technologies are being developed to take advantage of this route while maintaining patient autonomy and safety.
Patient-Controlled Analgesia
Patient-controlled intravenous analgesia (PCA) is a means of enabling a patient to control their pain management. It is a machine that can be filled with a syringe or tubing that is set to give doses of medication no sooner than a set period of time. Hitting the button before the allotted period results in no medication administration. It is a requirement that patients are competent to use the equipment and are alert, aware, and oriented. Additionally, only the patient has the right to push the button.
The principle of PCA relies on the therapeutic window. A proper loading dose is required to reach and surpass the Minimum Effective Analgesic Concentration (MEAC). It is at this point that patients note pain relief. If more opioid is given, the side effects of the medication become apparent. This is the toxic threshold, and there can be several toxic thresholds depending on the type of side effect. For example, nausea may occur at a certain concentration, while pruritus occurs at a different concentration, altered mental status, etc. Each individual has different thresholds based on their genotype and phenotype. It is possible to have patients with a toxic threshold below the MEAC; for example, one could have a patient who is nauseous but also needing more opioid for pain control. This is a patient who would benefit from analgesia from another receptor.
PCA machines allow for the setting of the following parameters:
Demand (bolus) dose
Lockout interval
Hourly limit
Continuous (basal) infusion
Nurses can additionally apply:
Rescue (loading) dose
Demand (Bolus) Dose
The demand dose is the amount of opioid the patient receives each time they activate the machine by pushing the button. The appropriate demand dose is small enough to minimize side effects, but large enough to provide effective analgesia.
Lockout Interval
The lockout interval is the amount of time set between the demand doses. During this time the patient cannot administer the opioid even if the system is activated. Lockout intervals between 5 and 10 min are commonly used.
Hourly Limit
To ensure further safety, an hourly limit is set for the maximum amount of opioid received by the patient. Hourly limits can be set for 1 h or more. An hourly limit is determined by the settings of demand doses and lockout interval.
Continuous (Basal) Infusion
Continuous infusions are not commonly used in acute pain, and only should be considered in select situations, such as opioid-tolerant patients who cannot achieve nocturnal pain control with other modalities. However studies have shown that nighttime basal infusions do not improve sleep or analgesia. Continuous infusions are avoided in high-risk patients, elderly patients, patient with sleep apnea, or the morbidly obese, as they are prone to developing respiratory depression.
Rescue Dose
While on a PCA, patients may require additional doses in times of intense nociception (dressing change, ambulation after surgery), or when the level of analgesia from a PCA is inadequate. These doses of opioids are termed as rescue doses, and are delivered by a healthcare provider.
Opioid Choices for PCA
Several opioids can be used in PCA (Table 24.5). The typical opioids include morphine and hydromorphone. The phenylpiperidines fentanyl, sufentanil, alfentanil, and remifentanil can only provide analgesic benefit for a short duration. When the volume of distribution of fentanyl is approached, however, the duration of relief can be similar to hydromorphone. Meperidine (pethidine in the UK) has fallen out of favor because of the neurotoxicity (lowered seizure threshold) of its metabolite normeperidine. The onset of action of methadone is so prolonged that its use in a PCA is questionable, although it has been used.
Table 24.5
Patient-controlled analgesia—common agents and suggested management
Drug | Demand dose | Lock out (min) | 1 h limit | Continuous/basal rate (if indicated) |
|---|---|---|---|---|
Morphine (1 mg/ml) | 0.5–1 mg | 6–10 | 10 mg | 0.5–1 mg/h |
Hydromorphone (0.2 mg/ml) | 0.1–0.2 mg | 6–15 | 2 mg | 0.1–0.5 mg/h |
Fentanyl (50 mcg/ml) | 10–50 mcg | 6–10 | 100 mcg | 10–50 mcg/h |
In the opioid-tolerant patient these doses will need to be individualized based on the amount of opioid the patient takes per day leading to higher initial demand doses and possibly the initial use of continuous infusions. High-risk patients, identified as elderly (age 70 or above), morbidly obese, or those with a history of obstructive sleep apnea, should have lower initial demand doses (e.g., one-half the usual demand dose) and opioid-sparing strategies are of utmost importance.
Monitoring and Management of PCA
Respiratory depression events can lead to anoxic brain injury or death. These are serious consequences and, therefore, safety measures and vigilance must be applied. The Anesthesia Patient Safety Foundation (APSF) has recommended the use of continuous monitoring of oxygenation (pulse oximetry) and ventilation in patients receiving PCA. Continuous monitoring should be used in all patients, especially for high-risk patients (elderly, obstructive sleep apnea, morbidly obese).
If the patient does not receive adequate pain relief with a given demand dose, one can increase the demand dose or decrease the lockout interval. In addition to talking to patients about their pain experience, one can collect objective data from PCA machines. One should have access to PCA usage, and some PCA pump manufacturers provide graphical data on opioid use, demand dosing, and allocation of doses when permitted. This data can be helpful to determine when patients experience pain, whether they are being undertreated, or whether there are behaviors that need to be examined.
Safety and Efficacy of PCA
While continuous infusions of opioids can lead to over medication and respiratory depression, patient-controlled analgesia has an inherent safety mechanism built in. That is, if the patient is getting sedated by the demand doses of the PCA, then he/she will not further activate the PCA machine. One of the major benefits of PCA is that it allows each patient to titrate the amount of opioid they receive. Furthermore, some degree of placebo effect may be imparted by the use of a PCA, thereby enhancing overall pain control. Other benefits of PCA over nurse-administered opioids include improved patient satisfaction, similar rates of side effects (except a higher incidence of pruritus), slight reduction in length of hospital stay, and a lower incidence of pulmonary complications.
Managing Side Effects of Opioids
Respiratory depression events are sentinel events and given their potentially life-threatening nature, mu-receptor antagonism is necessary to reverse this side effect. Since the half-life of naloxone is shorter than that of the opioid being reversed, a single dose of naloxone may not be sufficient; repeat doses or even a continuous infusion may be necessary. Reversal events result in a return of pain, and sometimes managing this pain is far more difficult than ever before in the patient’s course. Intensive monitoring of the patient should be initiated in these situations to ensure that the life-threatening event does not recur after the effects of naloxone have dissipated.
Constipation is a side effect of opioid therapy that does not gain tolerance with use. In fact, one such opioid, loperamide (imodium), is indicated for this purpose as an antidiarrheal. Prevention is paramount in all patients who require opioids, especially those on chronic therapy. Stool softeners, pro-motility agents, and osmotic agents are first-line options. Oral naloxone has limited systemic bioavailability due to first-pass glucuronidation and can antagonize the enteric mu-opioid receptors. Methylnaltrexone, a quaternary ion, is unable to pass across the blood–brain barrier. Thus, it causes peripheral mu antagonism to reverse opioid effects on the enteric system with preservation of central agonism and analgesic benefit. Another medication, alvimopan, has a high affinity for peripheral mu receptors and also does not significantly reverse analgesia.
Opioid-Induced Itch (OII) has historically been treated with diphenhydramine. Unfortunately, this has led to some dire consequences given the many ways that the drug works—antihistamine, anticholinergic, sedative, and hypnotic. It is on the Beers Criteria of drugs not to be used in patients greater than 65 years of age. The effect in children is often paradoxical, leading to hyperactivity, and some patients enjoy the hypnotic effects of IV formulation, and demand its use. If a patient develops urticaria, a hypersensitivity reaction, which can happen with drugs such as morphine or codeine, then diphenhydramine is appropriate. However, regarding opioid-induced itch, the leading theory currently is that there is a central mechanism in the medulla oblongata. While IV Benadryl should be specifically used for anaphylactic/anaphylactoid reactions, nalbuphine, a partial mu antagonist and kappa agonist, may be a useful option in that it partially antagonizes the mu receptor without clinically producing abstinence syndrome or a recrudescence in pain relief in the opioid tolerant. Butorphanol, a mixed mu agonist/antagonist and kappa agonist, has also been used in opioid- and non-opioid-induced itch. There has been mixed evidence with 5-HT3 antagonists. Some have also advocated a low-concentration propofol infusion, but clearly there are potential safety issues with this approach.
Opioid Conversion: Equianalgesic Potency
Opioid conversion is an important concept allowing healthcare providers to discuss the opioid tolerance of patients in a unified manner. This can be important in transferring care from one provider to another, or in opioid rotation. Below is a method to opioid conversion in acute and chronic pain settings. One must be mindful of the pitfalls in conversion. Historically, oral morphine has been the parent drug in which all other conversions can be made (Table 24.6).
Table 24.6
Equianalgesic dose of opioids
Drug | PO (mg) | IV (mg) |
|---|---|---|
Morphine (MS Contin) | 30–60 | 10 |
Codeine | 200 | – |
Fentanyl | – | 0.1 |
Meperidine (Demerol) | 300 | 75 |
Oxycodone (Percocet, Oxycontin)) | 20 | – |
Hydrocodone (Vicodin) | 20 | – |
Hydromorphone (Dilaudid) | 8 | 1.5 |
STEP 1: Calculate the daily opioid requirement. Include ALL of the opioids (oral, epidural, prn) administered.
STEP 2: Convert to ORAL MORPHINE. Use a table or an application, which can roughly provide good estimates.
STEP 3: ALWAYS CONSIDER INCOMPLETE CROSS-TOLERANCE. Cross-tolerance is the extension of physiologic resistance for a substance to others of the same type or class, even those to which the body has not been exposed. In most instances, cross-tolerance is incomplete and can range from 20 to 30 %.
STEP 4: THE PRICE IS RIGHT. Similar to the popular daytime game show, bidding/guessing a dose closest to the patient’s requirements wins. If one over bids, the game is automatically lost as going over when it comes to opioids can have disastrous consequences. When in doubt, start at a low dose and tailor as the patient’s pain dictates.
Acute Pain in the Opioid Tolerant
One should expect that opioid requirements for these patients will be significantly higher than in the opioid-naïve patient. The pain thresholds are lower with more pain complaints and higher pain scores are endorsed. It is important to know that this can be likely a result of not opioid tolerance, but of opioid-induced hyperalgesia. In addition to replacement of chronic baseline requirements, increased doses are required to provide any noticeable relief. Thus, discussion of reasonable goals and expectations of analgesic therapy with the patient is crucial. An Acute Pain Service can provide care for these patients as they can be challenging. These patients often know what agents have either worked or not worked for them in the past. The use of multimodal therapy in this patient population is especially important as opioid therapy alone will leave much to be desired.
Regional Anesthesia
The importance of regional anesthesia cannot be understated in acute pain management. Some of the pitfalls with regional anesthesia at this time include the time it takes to perform, the lack of quality in planning and performing blocks, and poor management of catheters once they are placed. For this reason, surgeons may have negative views of regional anesthesia. When done correctly, regional anesthetics are the best analgesics; in these situations, there are surgeons who demand regional anesthesia for their patients. The current trend in academic programs creating and developing regional anesthesia and acute pain fellowships demonstrates the growing awareness of the importance of regional anesthesia and the need for specialization. Currently, there are studies being done on long-acting local anesthetics, for example, depo local anesthetics and biologic sodium-channel blockers, such as saxitoxin. Providing days of relief rather than hours might be a significant leap in postoperative pain management possibly reducing the incidence of chronic pain after surgery.
Patient-Controlled Epidural Analgesia
From a physiologic standpoint, epidurals block action potentials of nerves. The concentration of the local anesthetic, in general, determines which nerves are affected. Small diameter nerves are more susceptible than larger diameter nerves. Therefore, at appropriate concentrations, epidurals will block A-delta and C-fiber transmission while sparing motor A-alpha nerve transmission. The C-fiber blockade leads to sympatholysis with the potential to increase renal, mesenteric, hepatic, and coronary blood flow, depending on the level blocked.
Patient-Controlled Epidural Analgesia (PCEA) serves the same principles as PCA in that the patient has control of their pain management. Despite numerous attempts, the ideal PCEA solution (commonly local anesthetics, opioids, and/or clonidine) and even the ideal delivery variables (similar to PCA—bolus volume, lockout time, hourly limit, basal rate) remain controversial. Commonly used local anesthetics include bupivacaine (0.0625–0.2 %) or ropivacaine (0.1–0.2 %), while commonly used opioids include fentanyl (1–4 mcg/ml) or hydromorphone (10–50 mcg/ml).
In distinct contrast to IV PCA where basal infusions are not commonly used, a continuous infusion is routinely used for PCEA (6–14 ml/h). By self-administering a bolus volume the patient may supplement, or “top off” their epidural during periods of increased pain. If multiple boluses are initiated each hour, patient will likely benefit from an increased basal infusion rate. However, should hypotension or dense motor blockade result, a more dilute local anesthetic solution may facilitate maintenance of this higher rate. If hypotension persists, the epidural infusion may need to be stopped, and alternate methods for pain control (IV PCA) may have to be used.
Patients with nausea and vomiting are treated with antiemetics or discontinuation of the opioid from the epidural solution. Pruritus is treated with nalbuphine (2.5–5 mg every 4 h prn). Persistent pruritus can be treated with a naloxone infusion (0.4 mg/l of IV fluid, about 250 ml/h). Generally, PCA therapy has a higher incidence of nausea and vomiting, while epidurals have a higher incidence of pruritus, urinary retention, and varying degree of motor block. Persistent motor block and back pain may indicate the development of epidural hematoma. The patient should have an immediate MRI to rule out the hematoma, and if diagnosed, should have an urgent decompression laminectomy.
The evidence thus far favors epidural analgesia for acute pain management in improving postoperative pain control, reducing postoperative pulmonary complications, reducing postoperative ileus, improving lower extremity graft survival, reducing incidence of deep vein thrombosis and pulmonary embolism, and decreasing time to mobilization and length of ICU and hospital stay. Further studies need to be conducted on whether epidurals can help ameliorate renal dysfunction. Other theoretical advantages, although not statistically proven at this time, include improved wound healing and decreased infection risk. The use of PCEA can lead to improved patient satisfaction.
Chronic Pain
Chronic pain is a disease. It is pain that persists beyond the expected period of healing. Historic definitions base it on duration: pain that lasts longer than 1, 3, or 6 months. Unlike acute pain syndromes, chronic pain is a more complex issue given the bio-psycho-social-genetic influences. While chronic pain is not a normal part of aging, it is widely accepted as so, which leads to under-treatment with resultant reduced quality of life, decreased socialization, depression, sleep disturbances, cognitive impairment, and malnutrition. As such, a multi-modality approach addressing these complex interrelated factors is necessary to achieve successful chronic pain management. The multi-modality approach to addressing chronic pain syndromes should utilize pharmacological, interventional, psychological, rehabilitation approaches, along with complementary and alternative medicine.
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