Introduction

Chronic pain is a leading chief complaint in an adult ambulatory care setting[1].  Patients should be evaluated for the nature of their pain both physically and psychologically in addition to how pain has affected every aspect of life.   The treatment goal of chronic noncancer pain (CNCP) is to improve function; therefore, setting expectations and providing education surrounding techniques to decrease pain intensity and frequency of flares to improve quality of life[2][3].

In Europe, many studies reported a significant influence of CNCP on different aspects of quality of life. Chronic pain impairs the patients’ perception of their general health, interferes in daily activities which results in withdrawal and isolation from family and friends thus increasing the risk of depression. Chronic pain has a detrimental economic impact as well which includes lost workdays. In a 6-month study, the average lost workdays were 7.8 with about 22% of patients in this study having a minimum of 10 missed workdays. These numbers increased when the patient had a major depressive disorder.[4]

There are pharmaceutical and non-pharmaceutical treatments for CNCP. In the management of CNCP, physicians should always consider a multidisciplinary approach to providing treatment options as chronic pain does not respond to medical monotherapy alone[4].  Treatment options include medications, interventions: both injection therapy and surgical, psychological therapy, physical therapy, and alternative complementary modalities which include acupuncture[4][5].

Management of CNCP ideally includes the involvement of different specialties to provide care including the primary care physician, pain specialist, psychologist, and physical therapist to provide education, therapy, and monitor progress[6].  

Etiology

CNCP can arise from many different stressors such as physical or psychological trauma(accident, death of a loved one), an infectious process such as Ebstein Barr virus (EBV), chronic underlying diseases such as sickle cell anemia or autoimmune conditions, or it can occur in the setting of multiple episodes of acute pain.  Risk factors for CNCP include a patient's depression, anxiety, substance dependency, disability, lower socioeconomic level, and low job satisfaction[1]. 

Chronic pain can come from repetitive acute insults but also can develop as its own distinct disease state[4].  Studies in human and animal models of chronic pain revealed functional synaptic changes in the brain and spinal cord[4].  These changes demonstrated a decrease pain threshold resulting in hyperexcitability of the nociceptive system and a decreased tone of the descending modulating system which is antinociceptive[4].  This results in an imbalance with increased nociceptive tone resulting in the manifestation of chronic pain[4].  

Epidemiology

A query of the National Health Interview Survey in 2016 reported 1 in 5 adults in the United States have chronic pain[1].  Women, adults with low socioeconomic status or on disability, and adults living in rural areas were over-represented in the chronic pain population[1].

About 20% of patients with CNCP who visit physicians’ offices receive an opioid prescription. Even though the efficacy of opioids in the treatment of pain for an acute or short period works, the use of opioids for long-term treatment of CNCP does not show a positive effect or improvement in the quality of life for patients. In 2005, based on data from the United States health system, an estimated 9.6 to 11.5 million adults (3% to 4%) of U.S. adults were prescribed opioids for long-term therapy.[8]

Using opioids for long-term therapy has risks of dependency and overdose. From 1999 through 2014, there were more than 165,000 deaths due to opioid pain medication overdose in the United States In 2011, the Drug Abuse Warning Network estimated that the misuse or abuse of narcotic pain medications caused more than 420,000 emergency department visits. [5]

Pathophysiology

The International Association of the Study of Pain revised the definition of pain which is verbatim as follows: 

• Pain is always a personal experience that is influenced to varying degrees by biological, psychological, and social factors.
• Pain and nociception are different phenomena. Pain cannot be inferred solely from activity in sensory neurons.
• Through their life experiences, individuals learn the concept of pain.
• A person’s report of pain should be respected.
• Although pain usually serves an adaptive role, it may have adverse effects on function and social and psychological well-being.
• Verbal description is only one of several behaviors to express pain; inability to communicate does not negate the possibility that a human or a nonhuman animal experiences pain.

Because pain is a psychosociobiological phenomenon, this definition outlines that pain can not be regulated solely by the activity of sensory neurons which is why it is inappropriate to dismiss a patient as "crazy" when an anatomical structural cause is not identified in the diagnostic workup for the pain. 

In reviewing the cellular underpinnings of chronic pain, there are pronociceptive changes evident when afferent nociceptive signals are amplified with a lack of descending modulation in the dorsal horn pathway.  Serotonin and norepinephrine act in descending modulation- bolstering this tone is used in chronic pain therapy. CNCP can occur from prolonged nociceptive stimulation, nerve injury, inflammation that can sensitize the pain transmission fibers, the death of inhibitory cells, or structural neuroplastic changes.   

Histopathology

In CNCP, cortical processes like alertness activate pain-facilitatory cells in the medulla. Different single-nucleotide-polymorphisms can generate more or less pain sensitivity. Functional MRI studies demonstrated that patients reported different pain levels for standard stimuli with varied activation of the anterior cingulate gyrus, frontal cortex, and somatosensory cortex[4]. This can explain the presence of chronic pain in a clinical syndrome like fibromyalgia in which central sensitization plays a role.  Other manifestations of central sensitization are complex regional pain syndrome which is a neuropathic pain condition usually isolated to an extremity.  Visceral hyperalgesia also demonstrates central sensitization which can be responsible for obscure pelvic, chest, or abdominal pain.

History and Physical

A comprehensive history and physical is necessary to determine the nature of the pain and its impact on life[4].  Specific questions about the pain can facilitate identifying a pain generator as outlined below:

• the context in which the pain started
• duration of pain
• pain location +/- radiating
• quality of pain- eliciting descriptors such as "aching, dull, sharp or burning",
• pain severity- using a numerical rating scale where 0 is no pain and 10 is the worst pain imaginable
• the timing of pain, whether constant or intermittent
• alleviating and aggravating factors                                                                                                                                                                                                                                                                                                              

Past medical history, and reviewing prior diagnostic testing and imaging provides valuable information on identifying the pain generator. Assessing other therapies tried for pain such as prior medications, interventions, therapies both physical and cognitive, alternative modalities, and response to these therapies are relevant to formulating a treatment plan. 

A thorough musculoskeletal and neurological physical exam are necessary systems to evaluate for pain.  Checking reflexes, strength, sensation, and gait can reveal deficits and compensatory movements patients adopt due to pain.  Assessing for tender points, trigger points, and hypermobility are relevant features to identify in patients with musculoskeletal pain.

Evaluation

It is recommended that physicians take the following steps in the management of such a patient:

• Create a list of complaints with priorities, and accentuate HPI and physical examination during the evaluation.
• Evaluate the patient’s symptoms while providing patient education
• Order imaging and diagnostic testing based on findings of the physical exam; if a physical exam is normal, additional testing is not required 
• Minimize the use of medications with dependency potential, especially short-acting medications that are used as needed.
• Reduce the use of passive modalities options for therapy.
• Schedule the patient's visits routine instead of as needed visits.
• Effectively treat any comorbid axis I (i.e., major psychiatric) disorders.
• Include cognitive therapy within the treatment plan

Treatment / Management

CNCP Management Options

Chronic pain often does not respond to medications alone.  Physical therapy with active modalities such as strengthening, cognitive therapy, injections, surgery, or alternative modalities like acupuncture should be included.  In selected cases, a surgical evaluation may need to be considered.

Medications such as non-opioid analgesics: anti-inflammatories, muscle relaxants, topicals, neuropathic pain agents which include antidepressant medications selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitor (SNRI), tricyclics, and gabapentinoids are frequently used in chronic pain therapy.[6] Antidepressant agents and gabapentinoids are used frequently in the medical management of CNCP and are discussed below.

Antidepressants 

The most common comorbidities with CNCP are anxiety and depression. Duloxetine and venlafaxine both are FDA-approved for general anxiety disorders. There is some evidence for the effectiveness of lamotrigine for post-traumatic stress disorder (PTSD), valproic acid for panic disorder, pregabalin for social phobia and generalized anxiety disorder, gabapentin for social phobia.

Antidepressants are more effective for pain caused by arthritis, post-herpetic neuralgia (shingles), fibromyalgia, diabetic neuropathy, peripheral neuropathy, spinal cord injury, stroke, radiculopathy, pelvic pain, migraine, facial pain, and low-back pain.

The mechanism of pain relief due to antidepressants is not completely understood. Antidepressants can cause an increase of neurotransmitters that reduce pain signals. Patients might feel the pain relief within 7 to 10 days, but the maximum effect is after several weeks. Tricyclics are the most common antidepressant used for pain control.

People with chronic pain are at high risk of developing depression. Some serotonin-norepinephrine reuptake inhibitors (SNRIs) like duloxetine (Cymbalta), venlafaxine (Effexor XR), and milnacipran (Savella) can be used in the same dosage to treat both CNCP and these comorbidities (depression and anxiety).

Tizanidine has an enhancing effect on the inhibitory function in the central nervous system (CNS) which causes pain relief as a muscle relaxant. Amitriptyline (Elavil) and nortriptyline (Pamelor) are members of the tricyclic antidepressants (TCAs) most frequently used to treat CNCP. The selective serotonin reuptake inhibitors (SSRIs) fluoxetine (Prozac), paroxetine (Paxil), and sertraline (Zoloft), and SNRI duloxetine (Cymbalta) are common medications prescribed for CNCP by healthcare providers.

Gabapentinoids

Gabapentin and pregabalin are used in neuropathic pain and fibromyalgia. Gabapentin and pregabalin acts on the alpha 2 delta receptor on voltage-gated calcium channels blocks that activate excitatory synapse formation.

The recommended dosing for gabapentin use in CNCP:

• Neurontin (short-acting gabapentin), the first day of treatment of 300 mg, doubled on the second day (300 mg twice a day), and tripled on the third day (300 mg three times a day). The dose can be increased as needed for pain relief to a maximum dose of 1800 mg daily (divided into three doses). Clinical studies referenced that effectiveness for a range of doses from 1800 mg/day to 3600 mg/day; however, there was no additional benefit seen with doses greater than 1800 mg/d.

Differential Diagnosis

Chronic pain can be confused for recurrent episodes of acute pain which could herald a larger disease process. Patients should be evaluated for autoimmune conditions and oncological processes through a complete review of systems.

Prognosis

The outcome of patients with CNCP is largely influenced by the patient's ability to cope and self regulate as pain and its subsequent impact occur at the level of the higher cortical centers [7] that is highly contextualized based on the patient's prior experiences.

Complications

There is no indication to use opioids in the treatment of CNCP however for many years, opioids have been the standard of care for the management of acute and chronic pain related to severe medical diseases like cancer. Due to the potential for abuse and addiction, the effectiveness of opioids in the treatment of CNCP has been controversial and challenging. Patients are overtreated or undertreated. There is little evidence to support the efficacy of opioids in the management of CNCP.

The limitation of data from most studies is that they exclude patients with a history of drug use or dependency, so clinicians do not have accurate information about the efficacy of opioids used for CNCP. Furthermore, the fact that using opioids can interfere with patients' employment status, functionality, and quality of life should force clinicians to consider other treatment options in the management of CNCP. Inadequate treatment of pain in patients with a previous history of dependency and addiction is also another management challenge of which physicians need to be aware. In this group of patients, there is a propensity for providers to attribute pain complaints and requests for pain medication to drug-seeking or addictive behavior instead of a true pain disorder.[11]

Deterrence and Patient Education

The  American Chronic Pain Association and the International Association for the Study of Pain offer resources for physicians https://www.theacpa.org/pain-management-tools/resources/professional-groups/ and patients https://www.iasp-pain.org/Education/Content.aspx?ItemNumber=1723.

Pearls and Other Issues

Chronic pain is the main cause of disability in the United States, and based on National Institute of Health report in 1998, lost jobs, healthcare costs, and lost productivity due to chronic pain cost estimated $100 billion annually. Usually, chronic pain cannot be prevented, but by staying in a good physical and mental health, individuals can reduce the risk of CNCP. There are multiple studies of chronic pain models:

• Persistent post-surgical pain (PPP)
• Persistent post-trauma pain (PTP)
• Post-herpetic neuralgia (PHN)

Diagnosing and treating the underlying cause of nervous tissue injury is vital. In one instance, using antiviral in early treatment of herpes zoster known to impair DNA replication of varicella-zoster virus (VZV) virus reduces the risk of occurrence of PHN. Also, an effort to limit tissue injury during procedures, careful dissection, the least invasive surgical approaches, and multimodal pharmacological methods to target the underlying mechanism of neuropathic pain are recommended to prevent PPP and PTP incidence.[14]

Studies have shown benefits of using gabapentin preoperatively for procedures like hysterectomies, thyroidectomies, and mastectomies to reduce the need for post-surgery analgesics and to reduce the incidence of PPP. In one study of patients with total knee arthroscopy (TKA), pre-surgery administration of pregabalin for 2 weeks resulted in the reduction of postoperative and chronic neuropathic pain at both 3 and 6 months, postoperatively. There was 0% incidence in the pregabalin group compared to the placebo group (8.7% and 5.2% at 3 and 6 months respectively).[15]

Enhancing Healthcare Team Outcomes

The management of chronic pain is complex and should be done with an interprofessional team that consists of a pain specialist, nurse anesthetist, primary care provider, neurologist, psychiatrist, radiologist, physical therapist and an anesthesiologist. With a major epidemic of opioid overdose currently ongoing in the US, healthcare workers are asked to refrain from prescribing these agents and seek other ways to combat pain. It is important to work as an interprofessional team because pain can be managed without opiates in most patients.[8]