Chronic Pain Syndrome

Article Author:
Rama Yasaei
Article Editor:
Abdolreza Saadabadi
6/27/2020 4:15:18 PM
PubMed Link:
Chronic Pain Syndrome


Chronic pain is one of the common reasons patients visit the doctor, During these appointments, physicians and all medical care professionals should evaluate patients for comorbidities such as depression and substance dependency. The purpose of treating chronic noncancer pain (CNCP) is not always to eliminate the pain; therefore,  it is important to communicate about the treatment plan and target. Important points to discuss include reducing the pain, improving quality of life, and increasing the patient's function.[1][2]

In Europe, many studies reported a significant influence of CNCP on different aspects of quality of life. Chronic pain negatively changes the patients’ perception of general health, interferes in daily activities which make patients participate less in these activities, and isolates patients from family and friends which increases the risk of depression. Chronic pain has an economic impact. These impacts include lost work days. In a 6-month study, the average lost work days were 7.8; although, about 22% of patients in this study had a minimum of 10 missed work days. 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 all treatment options, and if possible, to try to use the non-addictive options, especially when the patient has a history of substance abuse.[5]

Management of CNCP ideally includes different specialties including the primary care physician, psychiatrist, addiction specialist, pain specialist, psychologist, and pharmacist to provide the best treatment plan and goal for the patient.[6] An addiction specialist is one of the most important specialists to involve to monitor patients using drugs with dependency potential, identify the possible relapse, and evaluate these patients throughout the treatment.[3]


CNCP originates in various ways, for example, from trauma (accident, back strain due to heavy lifting), an underlying disease like pancreatitis, spine disease, arthritis, and autoimmune diseases, or it can occur with fibromyalgia or persistent migraines. There are many risk factors for CNCP. These include a patient's sociology, biology, and psychology, along with environmental factors. Some specific risks are depression, anxiety, substance dependency, disability, lower socioeconomic level, and low job satisfaction.


Chronic pain is defined in various ways, but based on the Center for Disease Control and Prevention (CDC) guidelines, pain that lasts more than 3 months or past the time of normal tissue healing is defined as chronic pain. The prevalence varies, National Health and Nutrition Examination survey from 1999 through 2003 estimated that 14.6% of adults in the United States have current localized or general pain lasting a minimum of 3 months.

In 2012, National Health Interview study showed 11.2% of adults in the United States suffer from daily pain. About 20% of CNCP patient who visits 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. [4]


Biology of pain can be defined by the concept of nociceptive pain that relates to peripheral stimulation and pain perception. Nociceptive pain is a gauge of nociceptor activation when afferent nociceptive signals are attenuated and amplified by descending tracts in the dorsal horn pathway. The pain is a representation of these events. When a patient complains of severe and acute pain, but the clinician cannot find a specific cause even after the workup is complete, they may suspect that the patient's complaint is not valid. 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.


In CNCP, cortical processes like alertness activate pain-facilitatory cells in the medulla. Different single-nucleotide-polymorphisms generate more or less pain sensitivity. One imaging study showed that patients reported different pain levels for standard stimuli; this demonstrated the varied activation of the anterior cingulate gyrus, frontal cortex, and somatosensory cortex. This can explain the presence of chronic pain in a disease like fibromyalgia is genuine due to central sensitization. The sensitization can lead to visceral hyperalgesia which can be responsible for obscure pelvic, chest, or abdominal pain. This kind of visceral hyperalgesia usually responds to treatment for neuropathic pain with antidepressants and pregabalin.

History and Physical

CNCP patients have a variety of complaints, and it is usually hard to address all the complains. It is common that patients with CNCP often complain of constant pain, function impairment in almost all activities, mood disturbance, and sleep issues. These may be consequences of socioeconomic, job loss, relationship and sexual problems, and social isolation. It is important to quantify the pain and other relevance problems in scales of zero to 10 (zero indicating no pain, and 10 indicating the worst pain they can imagine) and keep track of this scaling for each patient and compare it at each visit.

It is expected that the complaints are worse than physical findings, but suspicion does not exclude the diagnosis of CNCP.


Most patients with CNCP complain about different symptoms; therefore, there is the risk that the clinician may inappropriately ignore the patient’s symptoms as insignificant. 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 comforting the patient about the absence of worrisome pathology.
  • Lessen expensive or invasive test and treatment options.
  • 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.
  • Make the patient's visits routine instead of as needed visits.
  • Effectively treat any comorbid axis I (i.e., major psychiatric) disorders.
  • Include or recommend counseling and relaxation therapy.

Treatment / Management

CNCP Management Options

Opioids analgesics, non-opioid analgesics, benzodiazepines (which are not first-line treatment), cannabinoids, antidepressant medications (selective-serotonin reuptake inhibitors (SSRIs), SNRIs, tricyclic, several anticonvulsants), gabapentin, and psychological and behavioral treatments.[5]

Opioids Analgesics

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. ddue 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. Systemic reviews show little support for 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]

In a trial of 62 CNPN patients who were considered low-risk or high-risk for opioid abuse, researchers questioned patients whether they had cravings for their medications and what affected their cravings. They studied whether there was a connection between cravings and medication compliance. Each month at clinic visits as well as daily over a 14-day period patients reported their cravings. Both the low-risk and high-risk groups craved their medication often. This was related to urge, preoccupation, and mood. Paying attention to cravings may help prevent misuse and better assist with prescription opioid compliance.[12] 


Gianni et al. studied the buprenorphine transdermal delivery system (BTDS) for its effect on CNCP. While the specific aim of the study was to examine cognitive and functional scores in elderly treated with the BTDS, a secondary result was the effective analgesic activity and safety of BTDS in older patients. There was an enhancement in mood and a partial recovery to perform activities, with no negative influence on cognitive and behavioral capability.[13]


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 the 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. 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.


Gabapentin is effective on CNCP, especially neuropathic pain and fibromyalgia. However, the pain-lessening mechanism of action is unknown. One of the theories is that gabapentin blocks the new synapse formations by blocking the calcium channel alp2delta (a2d)-1 receptor in CNS 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.
  • Extended-release gabapentin that also is FDA-approved for post-herpetic neuralgia with a titration schedule that begins with 300 mg on day one, 600 mg on the second day, 900 mg on days 3 to 6, 1200 mg on days 7 to 10, 1500 mg on days 11 to 14, and 1800 mg on day 15 and beyond.
  • Horizant (extended-release product), can be started at 600 mg once a day for 3 days, tittered up to 600 mg twice daily from the fourth day. A daily dose of horizant greater than 1200 mg does not provide any additional benefit at the expense of side effects.

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.[6]


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