1. 
   

   What is your goal of pain therapy?

   
   
2. 
   

   How are you going to “measure” pain?

   
   
3. 
   

   Are you treating multiple pain issues or types of pain?

   
   
4. 
   

   Does this patient have comorbidities that will affect your pain care?

   
   
5. 
   

   What are the most appropriate and effective pain treatment options available?

Taxonomy

Any discussion on the diagnosis and treatment of pain must start with the definition of pain. The International Association for the Study of Pain defines pain as an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage.

Pain can be classified in multiple domains. The first is the classification based on the underlying etiology of the pain. Nociceptive pain refers to the direct tissue injury from a noxious stimulus. Inflammatory pain refers to the release of inflammatory mediators that perpetuate and modulate nociceptive input. Direct injury to nerves results in a third type of pain , neuropathic pain, whereby the nature of sensory transmission is altered and accompanied by pain frequently described as a burning type of pain. Although these are described as discrete types of pain, they more often represent a continuum of the same injury. Surgical incision is a model of nociceptive injury that produces an inflammatory response. Incising the primary nociceptors in the skin with subsequent development of inflammatory neuritis can result in neuropathic pain.

The second domain of classification refers to the anatomic location of pain. In this category, pain can be described as either somatic or visceral. Somatic pain refers to a well-localized sensation related to skin, muscle, and bone, whereby visceral pain is poorly localized and is usually in response to distention of the internal organs such as the colon or small bowel, or compression or inflammatory injury, which occurs in pancreatic cancer or pancreatitis.

The final domain classifies pain based on the temporal nature of the pain. Acute pain usually refers to a neurophysiologic response to a noxious stimulus, a response expected to resolve with completion of wound healing. In contrast, chronic pain persists beyond the expected time course of an acute injury and its repair process. Chronic or persistent pain does not simply suggest that a given time interval has passed. Rather, such a diagnosis implies development of multiple neurophysiologic changes that alter the fundamental balance between noxious stimuli and their inhibitory mechanisms. Such changes occur from the peripheral nerve to the dorsal horn of the spinal column, interneurons throughout the spinal cord, to the thalamus and cortical circuits. These changes ultimately result in remodeling in the organization of the central nervous system.

Evaluation of Pain

Pain is a subjective phenomenon and results from a patient’s understanding of the physical and affective impact the sensation has had on them. There are multiple quantitative pain evaluation scales. Although these are subjective reports with no way to verify the answer’s “truth,” these scales have been used for decades and correlate well to experimental and clinical pain responsiveness. Although the practitioner must be aware that the patient can manipulate the pain report, it is imperative to first validate the patient’s understanding of his or her pain by receiving his or her report with an unbiased view.

The numerical rating scale (NRS) may be the most commonly used tool for the evaluation of pain intensity. Patients are asked to rate their pain on a scale of 0 to10, with 0 translated as “no pain” and 10 the “worst pain imaginable.” Similarly, the visual analog scale (VAS) allows patients to mark a point on a 10-cm line that corresponds to the level of their pain. The 4-point verbal rating scale (VRS) asks patients to categorize their pain as none, mild, moderate, or severe. The VAS and NRS demonstrate excellent agreement, and both offer superior discriminating ability to the categorical VRS.

The above case study involves a patient with dementia, which can pose additional challenges for the evaluation of her pain. Standard pain reporting scales are ineffective for patients who suffer from dementia, who are unconscious, or who are unable to communicate. Pain scales such as MOBID-2, Checklist of Nonverbal Pain Indicators, and Doloplus 2 have each been designed for the patient with dementia or in an assisted living facility. These scales have strong conceptual and psychometric support, however they are an indirect measure of the patient’s pain and therefore at risk of the health care providers’ intrinsic biases.

Timing and activity are relevant to the interpretation of pain scores. Reported pain scores may refer to the past hour, 24 hours, week, or month. Average, maximum, and minimum pain scores help ascertain the patient’s range of pain. Pain scores may also be described as rest or static versus active or dynamic to correlate the given score with activity level. Pain scores reported by the patient when resting may not reflect pain-based limitations on activity. Because the goal of pain treatment usually includes improvement in mobility or function to decrease thromboembolic and pulmonary complications, addressing only rest/static pain may result in a failure to maximize the benefit of pain control.

The above scales are applied to all types of pain: acute, chronic/persistent, and cancer pain. The added complexity of chronic/persistent or cancer pain can require more multifaceted evaluation tools. Additional pain scales can be administered to these patients to better deliver more targeted pain care, but they will not be discussed as they are beyond the scope of this chapter.

Poorly controlled pain can present through multiple parameters including vital signs and laboratory values, reinforcing the impact of a patient under significant physiologic and psychological stress. Manifestations of this stress can include myocardial ischemia, immunosuppression, impaired wound healing, and thromboembolic events.

Treatment of Pain

Treatment of pain can utilize four primary modalities. These include medications, interventions, behavioral therapies and physical therapy/complementary treatments. This review will focus on the medical and interventional management of pain, although behavior and complementary treatments are essential components of improving the overall pain state in patients with persistent pain.

Systemic Analgesia

Opioids

Opioid medications remain the most common treatment for both acute and chronic/persistent pain. By activating the mu opioid receptor throughout the CNS, opioids modulate the perception and transmission of painful stimuli. Opioid-based therapies are not limited by a ceiling effect; increasing doses will theoretically yield increasing analgesic effects even at extremely high doses. However, increasing doses of opioids are functionally limited by side effects such as nausea, vomiting, constipation, sedation, and respiratory depression.

When used for acute pain, the most common routes of systemic opioid administration include intravenous (IV), intramuscular (IM), and per os (by mouth) (PO). Parenteral routes may also include transdermal (TD), subcutaneous (SC), transmucosal (TM), or iontophoretic/transdermal (ITD). Epidural and intrathecal administration is also used in a variety of settings.

Intravenous administration of opioids ensures a rapid, predictable onset and distribution of analgesic functioning, making this the favored route for the initial treatment of severe acute pain. Intramuscular and enteral routes may result in delayed onset of effects, limiting their effectiveness in the acute pain setting. Similarly, TD (ITD excepted) and SC routes of administration have considerably delayed onset and are more often appropriate for long-term use such as in chronic pain or palliative care settings.

Table 96-1 lists several opioids commonly prescribed for acute and chronic pain medicine. Commonly, patients will experience excellent pain relief following opioids administration. However, there can be a variable response to different formulations and pharmacologic compounds resulting from genetic polymorphisms involving mu-opioid receptor activation, receptor distribution, opioid metabolism, and the type of pain. Opioids are often best at treating static, nociceptive pain such as postsurgical pain, however they are less effective for dynamic or movement-related pain or neuropathic pain. Further, opioids are often ineffective in the treatment of bone fracture pain such as the pain experienced by the patient in the case study.

Opioid conversion: In the course of transitioning from severe acute pain to moderate, subacute pain, physicians will frequently transition the patient from parenteral to oral opioid administration.

1. 
   

   Calculate the patient’s 24-hour opioid use.

   
   
2. 
   

   Convert this to “parenteral morphine equivalent” (PME).

   
   
3. 
   

   The total oral dose prescribed to the patient is commonly less than 100% of the parenteral dose equivalent; this decision is guided by the clinical milieu of the patient including “the patient’s recovery from his or her pain.”

   
   
4. 
   

   Consider the division of this requirement into short- and/or long-acting opioids. This decision depends greatly upon the patient, the timing of his or her pain, and the nature of his or her pain.

   
   
5. 
   

   Fifty percent of the 24-hour PME can be given as a sustained preparation, and 50% as shorter-acting, immediate-release medications ordered as needed.

   
   
6. 
   

   To assist the physician with opioid conversion, numerous conversion tables and calculators are available (see www.hopweb.org).

Nonsteroidal Anti-Inflammatory Agents (NSAIDs)

NSAIDs exert their analgesic effect via inhibition of the cyclooxygenase (COX) enzyme, thus interfering with prostaglandin (PG) production. Prostaglandins modify nociceptive thresholds at both peripheral and central sites. By limiting production of PG from COX-1 and COX-2, NSAIDs offer effective analgesia for mild to moderate pain. Further, this mechanism of action apart from the mu-opioid receptor provides a strong supplement to opioids during treatment of moderate to severe pain. Although opioid sparing, NSAIDs do have a ceiling effect, beyond which increasing doses will yield no increase in analgesia. Clinically, NSAIDs decrease pain associated with orthopedic injuries, and those with extensive prostaglandin involvement such as pain from uterine contraction and muscle inflammation. However, the risk of bleeding and mixed evidence regarding interference with union of fractures and spinal surgery necessitates involvement of the operative team in the decision to add NSAIDs.

Traditionally, NSAIDs were nonspecific for the isoforms of cyclooxygenase, COX-1 and COX-2. COX-1 is constitutively expressed in nearly all human tissues, while COX-2 is focally expressed with inflammation. Blockade of COX-1 may promote development of gastrointestinal irritation and bleeding. NSAIDs as a class may also interfere with autoregulation of renal perfusion. To minimize the effects of gastrointestinal irritation and bleeding, drug development turned to selective COX-2 inhibitors. Although effective in minimizing gastrointestinal bleeding, selective COX-2 inhibitors may result in a prothrombotic milieu that may increase the risk of myocardial infarction.

Acetaminophen may represent a special class of NSAIDs. While its mechanism of action is not completely understood, there is evidence of antagonistic activity against COX-2, and a splice variant of COX-1 named COX-3. Notably, acetaminophen appears to not inhibit peripheral COX-1, which may explain its favorable safety profile in regards to gastrointestinal, hematological, cardiovascular, and renal effects seen with other NSAIDs and selective COX-2 inhibitors.

In assessing comparative efficacy, the number of patients needed to treat (NNT) for at least a 50% reduction in pain after 4–6 hours for 1 g of acetaminophen is 4.4, which compares favorably to 650 mg of aspirin or 100 mg of ibuprofen. A more typical dose of ibuprofen, 400 mg, however, had an NNT of only 2.3. Celecoxib, a selective COX-2 inhibitor, has a NNT of 4.5 at 200 mg when compared with placebo for postoperative pain.

Ca-Channel Antagonists (Anticonvulsants) and Tricyclic Antidepressants

Anticonvulsants such as gabapentin and pregabalin have found an increasing role in the treatment of chronic pain stemming from neuropathy. While designed to mimic the structure of gamma-aminobutyric acid (GABA), gabapentin does not actually bind to GABA receptors. Instead, its antihyperalgesic/antiallodynic effect likely stems from binding to the of alpha2delta1 accessory unit of voltage-dependent Ca2 channels within the dorsal root ganglia of the spinal cord, which are upregulated following peripheral nerve injury. By inhibiting these calcium channels, gabapentin and pregabalin my inhibit glutamate release from primary afferent nerve fibers, which activate pain responsive neurons within the spinal cord. Although gabapentin and pregabalin are effective for a myriad of chronic pain conditions, their role in acute pain management is less clear. The gabapentinoids have a clear role in the treatment of postoperative pain when given in the perioperative period (pre- and postoperatively) in a number of major orthopedic and gastrointestinal surgeries. In the acute and chronic pain setting, they have been shown to be opioid sparing and show promise as successful adjuvant analgesics.

Although developed initially for the treatment of depression, low-dose tricyclic antidepressants (TCA) are a mainstay of treatment for many chronic pain states, especially those involving neuropathic pain. Even though their mechanism of action remains unclear, TCAs may augment descending serotonergic and noradrenergic bulbospinal pathways on the dorsal horn of the spinal cord. This class of drugs has significant anticholinergic side effects, so in this case study (elderly and history of dementia), it would be contraindicated to use TCAs. They are titrated to goal dosing to gain benefit while decreasing the side effect profile. One advantageous side effect is somnolence, which is utilized by evening dosing and can facilitate sleep and decrease pain.

Patient-Controlled Analgesia

When compared to intermittent bolus dosing of opioids, IV patient-controlled analgesia (PCA) offers significantly greater analgesia and satisfaction. Both the strengths and risks of PCA systems depend upon a negative feedback loop: when in pain, the patient self-administers potent analgesics leading to pain relief, therefore limiting further opioid demands. An additional benefit of PCA dosing is that the patient is not dependent upon administration variables and has constant access to the prescribed dosing.