Transitional Pain Medicine: novel pharmacological treatments for the management of moderate to severe postsurgical pain

Overview

Unrelieved pain, hospital readmission, and persistent opioid use in patients discharged with complex pain reflect gaps in care following surgery. 10–20% of postsurgical patients are discharged without appropriate pain specialist follow-up to manage their complex postsurgical pain and to appropriately wean opioid medications. These patients often seek prescription re-fills from surgeons, primary-care, and/or walk-in clinics. Wait times for acceptance into specialized pain centers can be months. Multimodal analgesic regimens are implemented after major surgery via acute pain programs, but these regimens end once patients are discharged regardless of the patients’ pain state. This article discusses pharmacological candidates and introduces novel non-pharmacologic interventions for the treatment of acute postsurgical pain that aim to modify postsurgical pain trajectories and reduce the risk that an acute pain becomes chronic after surgery. The reduction of persistent opioid use following surgery by implementing transitional pain medicine interventions is a public health priority.

Comprehensive perioperative care

After major surgery, most patients have a time-limited course of moderate to severe acute pain that eventually dissipates so that they are able to return to their baseline level of functioning. However, there is a subset of patients (5–10%) that develop moderate to severe chronic postsurgical pain (CPSP) one year after surgery [1], and a subset of these patients are at an increased risk for persistent long-term opioid use.[2] CPSP has been estimated to incur annual direct and indirect costs of $41,000 annually per patient.[3] Research over the past decades have identified risk factors that predispose patients to the development of CPSP.[4–7] With the knowledge to date, the time has come to move beyond identifying risk factors. The field of perioperative medicine should be focused on the implementation of strategies aimed not only at the reduction of acute pain, but also on effective strategies for reducing the development of CPSP and long-term pain disability as a consequence of surgery. Our pain research unit has published a roadmap to the implementation of a world first Transitional Pain Service (TPS) dedicated to comprehensively addressing the problem of CPSP at three stages: (1) preoperatively, (2) postoperatively in the acute pain setting in-hospital, and (3) postoperatively in an outpatient setting for up to 6 months after surgery.[8] The priorities of the TPS are to comprehensively treat pain and improve patient functioning for patients at increased risk for developing chronic postsurgical pain, and manage/ wean opioid-based medication for medically challenging patients back to baseline or completely off post-discharge. A comparison will be made by analyzing the effectiveness for the TPS interventions for patients that have been involved with our program versus those that have declined within our institution and plan a linked analysis to other Ontario-based academic centers.

The Current State of Treatment for the Complex Acute Postsurgical Pain Patient

Poorly controlled postsurgical pain is a risk factor for hospital readmission and increased health-care resource utilization.[9] Patients with poor postoperative pain control who use opioids are often overlooked for months after hospital discharge, and at best are referred to chronic pain centers/specialists 12–18 months after the pain has become chronic and may be too late to modify the pain trajectory depending on the surgical injury. There has been a 402% increase in individual opioid consumption from 1997–2007 in the United States, a significant portion of which stems from chronic use after initiation of medical treatment.[10] Our group has demonstrated that 3.1% of patients who had never taken opioids prior to hospital admission (i.e. opioid-naïve) remained on opioid medications more than 3 months after their major surgical procedure.[2] The development of CPSP is presumed to be the major driver of persistent opioid use. Specific surgeries have higher risks of persistent opioid use (~10% with persistent use after thoracic surgery). In addition, patient-related factors predict higher risk of prolonged opioid use including younger age, lower income, comorbidities (diabetes, heart failure), and preoperative medications (benzodiazepines, antidepressants).[2]

The situation is far graver for patients taking opioids before surgery. Opioid-dependent patients typically leave hospital with a 100–300% increase in opioid medication dose from baseline following major surgery, typically without appropriate follow-up or a weaning plan. High-dose opioid use in this context is closely linked with increased risk of mortality.[11,12]

Novel strategies to reduce postsurgical pain: the development of a TPS to address a gap in the treatment of complex postsurgical pain patients

The TPS at the Toronto General Hospital (TGH) is composed of a multidisciplinary team of chronic pain specialists, nurse practitioners, psychologists, physiotherapists (with acupuncture and myofascial release training), and patient care coordinators.[8] The goal of our transitional pain program is twofold: (1) to modify the pain trajectories of patients who are at increased risk of developing chronic postsurgical pain and (2) to reduce opioid consumption long term, which is often overlooked in our typical course of current perioperative care.[13,14] There exists two subsets of patients that are treated by our service:

(1) The opioid-naïve patient without a preexisting pain condition has a 5–10% risk for the development of moderate to severe CPSP.[1] Opioid-naïve patients that have moderate to severe acute postoperative pain,[15] increased perioperative opioid use [16], preoperative negative affective states such as posttraumatic stress disorder,[17] depression,[18,19] anxiety,[7,20,21] and pain catastrophizing [22,23] are all candidates for our TPS given their increased risk to develop persistent pain and pain disability as a consequence of their surgical intervention.

(2) The patient presenting for surgery with a preexisting pain condition who are on a preoperative opioid medication. This population ranges from 10% to 20% depending on the institution (12.5% at the TGH).[8] These patients must also deal with their ‘acute on chronic’ postsurgical pain. Typically they leave the hospital after extended lengths of stay on significantly more opioid medications than they were taking during their preadmission visits. They continue on their increased opioid regimen without a plan to wean and often at a new threshold of medications.

Economic impact from the development of chronic postsurgical pain at Toronto General Hospital

These two groups of patients treated by the TPS encompass only 15% of patients that flow through our surgical services. The majority of surgical patients do not develop a significant acute pain problem or exacerbate a previous pain problem. However, if this 15% of complex pain patients proceed to develop CPSP and experience significant pain disability or persistent opioid use, they will consume 90% of our pain-related health-care resources. There are 6,000 surgeries performed per year at the TGH. 4,000 are major surgical operations, using a conservative model of a 5% incidence of moderate to severe pain and a conservative Canadian estimate of $7,000 in direct heath-related costs post discharge results in a 1.4–2.8 (10%) million dollar hit to the health-care system. Assuming an extremely conservative increase in direct costs for 60% as opposed to the 80–90% as our data suggests, the incremental cost could be an additional 1.5 million dollars to the health-care budget. CPSP developing from our institution alone could cost the Canadian health-care system 2–4 million dollars in annual incremental costs. When we extrapolate this data to the 230 million people worldwide undergoing surgery annually, the cost from the development of CPSP totals in the hundreds of billions of dollars.[24]

Novel pharmacologic interventions for the prevention of chronic postsurgical pain

There are no clear guidelines for dealing with the management of postoperative pain as patients leave hospital and recover for 3–6 months,[25] or on postoperative opioid prescriptions as patients progress from the hospital setting to the community.[26,27] The TPS utilizes novel pharmacological approaches for patients suffering from moderate to severe acute postsurgical pain. Patients with intense pain, who continue to be seen by the APS for longer than 4 days, consume more than 90 mg/day of oral morphine equivalents are treated by the TPS. Other clinical scenarios that trigger TPS involvement include (1) stable patients unable to be discharged due to a complex pain problem, (2) patients being discharged with a prescription for a long-acting opioid-based medication, (3) patients admitted on methadone or buprenorphine, (4) patients needing interventional postsurgical procedures (e.g. stump catheters post amputation), and (5) patients requiring a repeat anesthesia acute pain consultation once the APS has signed off prior to hospital discharge (triggered by the surgical team). These complex pain patients who are discharged with high doses of opioid-based medications often require assistance to be weaned beyond their hospital stay [28] and may require adjunctive therapy for neuropathic pain.

As Hayes et al. demonstrated over a decade ago, patients who were identified with acute neuropathic pain by their acute pain service are at risk of experiencing ongoing pain: 78% at 6 months and 56% at 12 months after surgery.[29] A similar trend in patient trajectories was found within the TPS at TGH.[8] For this reason, we utilize the revised Canadian chronic neuropathic pain guidelines [30] for patients who have significant acute neuropathic pain in the immediate postoperative time period. Once complex pain patients are discharged from hospital with follow-up to the TPS, their first outpatient visit is often within 2–3 weeks. If patients present with acute neuropathic pain symptoms at this visit, they are initiated on a first-line neuropathic pain agent (an α-2-δ agonist (gabapentin or pregabalin), a serotonin norepinephrine reuptake inhibitor, or a tricyclic antidepressant). In addition, we aim to improve patient trajectories with the implementation of aggressive psychological interventions (i.e. Acceptance and Commitment Therapy) [31] aimed at modifying patients’ pain experience and behaviors related to their pain.

Ketamine (an NMDA antagonist) appears to be the pharmacologic agent with the most consistent positive preventive analgesic results. [32] A comprehensive systematic review for the prevention of chronic pain after surgery in adults identified ketamine as the most reliable pharmacological agent for the prevention of CPSP.[33] At TGH we have implemented a strategy aimed at running ketamine infusions in high-risk patients beyond the operating room. Other Canadian institutions run low-dose ketamine infusions (i.e. 0.05–0.2 mg/kg/hr) for patients with preexisting chronic pain conditions and that are consuming typically greater than 80 mg of oral morphine equivalents daily in the postoperative setting without significant patient side effects. Other novel pharmacological agents have facilitated weaning patients from high amounts of opioid medications. A patient post liver transplantation followed by our TPS was weaned from his opioid medications by initiating medical cannabis. Beyond a significant reduction in opioid-based medications, the patient reported a significant reduction in his neuropathic pain symptoms using a cannabidiol (CBD) [Avidekel (MedReleaf), an indica dominant strain (THC 0.79, CBD 17.08%)]-based medical cannabis compound. Further studies are needed to support the use of medical cannabis during the transitional pain period.[34]

Future developments/treatments

The TPS at TGH will have data to support which pharmacological interventions reduce the incidence of chronic postsurgical pain. Strategies aimed at preventing chronic postsurgical pain should not only be implemented postoperatively, instead high-risk patients should be identified a priori and interventions need to be tailored to specific comorbidities preoperatively. Comprehensive programs that combine novel preventive pharmacological strategies, prehabilitation, mindfulness, cognitive behavioral therapy, and yoga could affect the long-term trajectory of patients following major surgery. Once discharged from hospital, one of the largest gaps in postsurgical care is the length of time between postsurgical follow-up visits (typically 6–8 weeks for surgeons). Integrating e-health and mobile technology into the TPS could improve the assessment and management of pain after discharge. Remote monitoring of patients’ pain and opioid usage on a daily basis by TPS physicians and allied health could lead to the optimization of patient care. Eventually predictive algorithms and alerts via mobile technology could indicate to caregivers that a patient needs an urgent intervention while out of hospital.

The past decades have focused on identifying risk factors that predispose patients to the development of increased acute/chronic postsurgical pain. We now need to focus on treating pain aggressively with both pharmacological and non-pharmacological interventions in patients who are at high risk for developing CPSP. Thus far, the development of CPSP and the associated cost to the patient and the health-care system have been overshadowed by the cost associated with treating chronic pain in the general population because CPSP patients have been embedded within larger chronic pain clinics. Therefore, the impact and magnitude of chronic postsurgical pain has been underappreciated. An estimated 60 billion dollars annually is spent in the United States and 6 billion dollars in Canada as a consequence of CPSP; this represents a significant public health expense. We aim to make significant in-roads with respect to the reduction of CPSP and persistent opioid use using our novel approach to perioperative care.[8] Although significant advances in pain genetics are more than 5 years away, it is hoped that a worldwide consortium focused on studying chronic postsurgical pain and collecting the DNA of patients that transition to chronic postsurgical pain will lead to the development of novel therapeutics to improve the treatment of CPSP and other chronic neuropathic pain conditions.[35]

CPSP can result from essential, life-saving surgery and it would never be suggested that surgery not be performed in these situations. However, acceptance and acknowledgment by surgical teams that CPSP is a potential consequence of surgical intervention are of upmost importance. Proper preoperative preparation of patients with psychoeducational workshops and pain optimization can empower patients with respect to their surgical intervention and will go a long way toward reducing the development of CPSP, pain disability, and persistent opioid use. Close monitoring of patients in the acute postoperative setting and timely identification/intervention of the 15% of surgical patients who are not recovering appropriately will be the key to modifying patient pain trajectories and reducing persistent opioid use after surgery.

Financial & competing interests disclosure

H Clarke is supported by a Merit Award from the Department of Anaesthesia at the University of Toronto. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Acknowledgments

H Clarke would like to thank all of his colleagues engaged in the daily clinical running of the Transitional Pain Service at the Toronto General Hospital. A particular thank you to Mr. Michael Poon and Dr. Ainsley Sutherland for their time spent reviewing this manuscript.