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Pain (Chronic)

Pain Management

The scientific approach to pain management demands a step-wise approach, which utilizes lower risk interventions first. In many cases, these lower-risk interventions are helpful for relieving chronic pain. For example, a recent review found that exercise and behavioral therapy were effective at decreasing pain and increasing functioning among patients with chronic pain (Hassett 2011). Other nonpharmacologic interventions that may be useful for chronic pain include meditation, biofeedback, acupuncture, electrical stimulation, and surgery (NIH MedlinePlus 2012). However, in those cases that do not respond to initial pain management treatment options with lower risk interventions, patients with chronic pain may have no other choice but to initiate pharmacologic therapy.

Pharmacologic therapy is one of the most popular treatment options for managing chronic pain. While initial treatment recommendations will vary based upon diagnosis (e.g., nociceptive vs. neuropathic), the most commonly used agents include (Bajwa 2012):

  • Non-opioid analgesics (acetaminophen and/or NSAIDs)
  • Opioids
  • Antidepressants (tricyclics and serotonin-norepinephrine reuptake inhibitors [SNRIs])
  • Antiepileptic drugs (gabapentin, pregabalin, and other anticonvulsants)
  • Muscle relaxants
  • Topical analgesic agents

The Potentially Lethal Side Effects of Over-the-Counter Pain Medications

In an effort to relieve suffering, many chronic pain patients turn to over-the-counter analgesics such as acetaminophen or non-steroidal anti-inflammatory drugs (NSAIDs) (Hersh 2007). However, since these drugs do not require a prescription from a doctor, patients may incorrectly assume that they do not need to be as careful about dosing as they would with a prescription analgesic. Therefore, it is important for chronic pain patients to become educated about the most serious adverse side effects that can occur with popular non-prescription analgesics (Wilcox 2005).

Since it was first marketed in 1955, acetaminophen has become one of the most widely used analgesics in the United States. In 2008, approximately 25 billion doses of acetaminophen were sold in the US alone (FDA 2009). Although acetaminophen can be safe when used appropriately, it can also be extremely dangerous. For example, unintentional acetaminophen overdose is responsible for approximately 15,000 hospitalizations each year, and is the leading cause of acute liver failure in the US (Woodcock 2009). Patents taking acetaminophen should follow these recommendations (Saccomano 2008):

  • Do not exceed a maximum dose of 4 grams/day
  • Remember that many prescription pain medications also contain acetaminophen
  • Recognize that acetaminophen is also called APAP, paracetamol, and acetyl-para-aminophenol
  • Do not use with other NSAIDs (without medical consultation), which increases the risk of kidney toxicity
  • Do not take with alcohol, which increases the risk of liver toxicity

NSAIDs such as ibuprofen and naproxen can significantly reduce pain associated with a variety of conditions. However, NSAID use is also associated with significant adverse effects such as gastrointestinal bleeding, peptic ulcer disease, high blood pressure, edema (i.e., swelling), kidney disease, and heart attack (Peterson 2010). For example, long-term use of NSAIDs can lead to impaired glomerular filtration, renal tubular necrosis, and ultimately chronic renal failure by disrupting prostaglandin synthesis, which can impair renal perfusion (Weir 2002). Even in NSAID users without overt kidney dysfunction, subclinical irregularities in kidney function are sometimes observed (Ejaz 2004).

Aspirin (a type of NSAID) is commonly used to treat minor aches and pains, as well as being prescribed at low doses (i.e., 81 mg daily) for heart protection and stroke prevention. Aspirin irreversibly inhibits an enzyme called cyclooxygenase-1 (COX-1) in platelets, which is why it poses a greater risk of bleeding (i.e., hemorrhage) than other NSAIDs (Hersh 2007). Therefore, patients taking aspirin should avoid the simultaneous use of anticoagulant drugs and/or alcohol (without talking to their doctor first). In addition to bleeding, aspirin can also cause side effects such as heartburn, nausea, vomiting, stomach ache, ringing in the ears, hearing loss, and rash (NIH 2011). See Figure 1 for more information about the role of cyclooxygenase in inflammatory reactions.

Despite the wide variety of pharmacologic therapies available for patients with chronic pain, a recent report published by an international panel of experts has pointed out that current conventional treatment schemes are lacking in efficacy and often impose unacceptable side effects (Coluzzi 2011). For example, opioids are the most commonly prescribed class of medication in the United States for short-term relief of chronic pain, and yet, their efficacy and negative side effect profile have many experts questioning their use in this way; especially since the increase in opioid availability has been accompanied by an epidemic of opioid abuse and overdose (Von Korff 2011; Friedrich 2012). In addition to the potential for dependence, patients beginning opioid therapy should also be aware of other common side effects, which include (Friedrich 2012):

  • Constipation
  • Nausea
  • Excessive sleepiness
  • Itchiness (i.e., pruritus)
  • Headache
  • Respiratory depression

According to the World Health Organization’s (WHO) "analgesic ladder", opioids are not recommended for chronic pain unless the pain can be described as moderate to severe, and/or has not responded to previous (non-opioid) treatment approaches. Consensus xxpert guidelines only recommend opioid therapy for managing chronic (non-cancer) pain once all other reasonable lower risk and lower cost pain management interventions have failed (WHO 1990; Chou 2009).

In an effort to reduce the risk of serious adverse outcomes associated with narcotic pain relievers, Congress has recently mandated that the FDA create the Risk Evaluation and Mitigation Strategies (REMS), which requires drug companies to develop special educational programs for physicians and for patients who are prescribed these potentially dangerous medications (Okie 2010). While opioid therapy can be used for chronic (non-cancer) pain in a safe way, it must be initiated properly, and only in select patient populations (i.e., physicians should carefully screen for mental disorders and history of substance abuse) (Edlund 2007; Chou 2009).

Opioids & Endocrine Dysfunction

Evidence linking long-term opioid use to a decline in endocrine function and subsequent hormonal imbalance has been accumulating for some time now, but recent data have garnered renewed attention (Katz 2009).

The molecular structure of opioids makes them well equipped to interfere with the normal function of the endocrine system. Evidence suggests this influence occurs in the hypothalamus and pituitary gland (brain regions) and the gonads (reproductive organs). Opioids tend to decrease gonadotropin-releasing hormone (GnRH) secretion from the hypothalamus, in turn decreasing the release of luteinizing hormone (LH) and follicle stimulating hormone (FSH) from the pituitary gland (Katz 2009).

This up-stream disruption has significant implications, especially concerning the ability of the endocrine system to produce additional hormones that rely on steady levels of GnRH, LH, and FSH. As a result of this hypothalamic-pituitary-gonadal axis suppression, the long-term use of opioids is associated with the development of hypogonadism (Katz 2009; Aloisi 2009). Opioids have also been known to reduce testosterone levels, which is associated with increased cholesterol levels and decreased insulin sensitivity (Woodall 2011).

Fortunately, most of these abnormalities can be identified through hormone level testing as well as patient history and physical examination. The following table summarizes some common endocrine-related problems associated with long-term opioid use (Woodall 2011; Vuong 2010; Merza 2010):

Common Endocrine-Related Problems Associated With Long-Term Opioid Use
Decreased body hair Infertility
Adrenal dysfunction Decreased libido
Decreased growth hormone Osteoporosis
Miscellaneous hormonal abnormalities Depression
Erectile dysfunction Missed menstrual periods

The three main therapeutic options available for patients experiencing these side effects are (Woodall 2011):

  1. Switch to a different type of opioid (i.e., opioid rotation);
  2. Switch to a non-opioid analgesic; or
  3. Initiate hormone replacement therapy (HRT). A recent study among male chronic pain patients concluded that long-term testosterone replacement therapy was associated with an increased quality of life and decreased pain ratings (Aloisi 2011).

Centrally-acting Drugs for Pain Relief

Chronic activation of peripheral pain sensors (nociceptors), such as occurs in osteoarthritis, for example, can alter central neural pain processing over time. The ongoing nature of chronic pain, and the adaptive nature of the central nervous system both contribute to biochemical alterations that increase pain sensitivity and cause the brain to become accustomed to processing pain. This phenomenon is known as central sensitization.

When the central nervous system has become "sensitized" to pain, painful sensations can be augmented because they are no longer only a nociceptive response, but are now being reinforced by mechanisms within the brain and spinal cord (Mease 2011).

Thus, chronic pain has a peripheral and a central element.

Evidence shows that patients with osteoarthritis of the knee are more sensitive to pain at other sites on their body than are healthy controls (Bradley 2004). This is because the brains of people afflicted with chronic pain have adapted to processing pain and have become hyper-responsive to painful stimuli.

The central element of chronic pain does not respond to traditional therapies such as anti-inflammatory drugs because they cannot modulate the transmission of pain within the sensitized central nervous system. Therefore, drugs such as antidepressants and antiepileptics can complement traditional anti-inflammatory drugs by modulating central biochemistry.

In the case of antidepressant drugs, it appears that the mechanism by which they provide pain relief is somewhat independent from their mood-altering affects (McCleane 2008), while antiepileptics alter pain signaling by modulating calcium signaling in the brain, which is also a mechanism by which they control seizures (Mease 2011).

For many people with chronic pain, centrally acting drugs are effective adjuvants to traditional pain therapies. Moreover, because central processing is a critical element of neuropathic pain, centrally-acting drugs are a mainstay of treatment in this setting (Yalcin 2009).