Background

Opioids are considered the gold standard therapy for acute pain and are the primary therapy for alleviating moderate-to-severe pain within the perioperative period (beginning from admission for a surgical procedure until discharged home). Chronic exposure to opioids can lead to a state of adaptation known as tolerance where an increased dose over time is needed to maintain the desired analgesic effect.1 Management of acute pain in adult opioid-tolerant patients perioperatively can be a challenging task as few interventions have reduced opioid requirements or pain scores within the population.2 The prevalence of prescription opioid use and opioid abuse makes perioperative pain management difficult as opioids are first-line therapy for alleviating moderate-to-severe pain. One study indicated that 44% of patients prescribed an analgesic for chronic pain were prescribed an opioid.1 While no clear definitions on opioid tolerance exist, researchers suggest that patients receiving or self-administering opioids for as little as two weeks prior to surgery may exhibit opioid tolerance.3 The United States Food and Drug Administration quantifies opioid tolerance as the use of greater than or equal to 60 mg of oral morphine equivalents per day for a period of seven days or longer.4 Fentanyl, meperidine, morphine and hydromorphone are opioids commonly used in the perioperative period and are among those most abused.5

The current systematic review will focus on orthopedic surgical procedures as they are considered among the most painful.5 In the perioperative period, healthcare professionals generally hold two prevailing views regarding opioid administration in the opioid-tolerant patient. The first is to offer higher doses of opioids to overcome a presumed tolerance. Administering high doses of opioids can lead to excessive sedation, nausea/vomiting or hyperalgesia (excessive sensitivity to pain, specifically opiate-induced hyperalgesia [OIH]). To a lesser degree, the second viewpoint is to modify or limit opioid use to prevent contributing to a greater tolerance, addiction or adverse effects.3 Administering low-dose opioids to opioid-tolerant patients can result in undertreatment of pain and physiological withdrawal symptoms. Both approaches can result in inadequate postoperative pain control and unacceptable side effects. With an estimated global population of between 26 and 36 million opioid users, and one million long-term users of heroin, treatment of the opioid-tolerant patient requires a different strategy than the patient not taking opioids (opioid-naive).6,7

Opiate-induced hyperalgesia paradoxically makes the patient more sensitive to pain, resulting in a hyperalgesic state that is resistant to increased opioid administration. Dupen et al.8 refers to OIH as a paradoxical increase in atypical pain unrelated to the original nociceptive stimulus and denoted recent research indicating an overlap of OIH and tolerance.8 Patients receiving long-term opioid therapy for chronic pain require, on average, about three times the opioid requirement of opioid-naive patients.1,9 Chronic exposure to opioids results in the need to escalate doses in order to achieve the desired analgesic effect resulting in a pharmacological tolerance. The same pharmacological tolerance can be seen in the opioid abuser. While ultrahigh and ultralow opioid dosing indicated no relationship between dosing and the triggering of OIH, large opioid doses appear to trigger OIH and tolerance more rapidly.9,10 Peripheral, systemic and intrathecal routes of administration all contribute to the development of OIH.10

In the clinical setting, it is common practice to administer higher doses of opioids to overcome a presumed tolerance. However, repeated dosing of opioids can lead to side effects such as respiratory depression, excessive sedation, bowel dysmotility and the possibility of worsening pain through triggering OIH.11 Pain refractory to traditional doses of narcotics leaves few options. Sensitization of the central nervous system (CNS) is associated with pain hypersensitivity as the N-methyl-D-aspartate receptor (NMDA) is specifically linked to the CNS's facilitation of pain processing.12 As the molecular mechanism believed to link tolerance and hyperalgesia is at the NMDA receptor, persistent nociceptive and neuropathic pain may be modulated through the NMDA receptor.10,13

Chronic pain patients on long-term opioid therapy may suffer inadequate postoperative pain control. Despite three-fold greater opioid consumption, pain management in the opioid-tolerant patient remains a challenge, as 20-30% of patients experience moderate-to-severe pain following surgery.1 Inadequate pain control is linked to complications that affect both the recovery period after in-patient surgery and delayed discharges after ambulatory surgery.1,14

Ketamine is a phencyclidine derivative that is utilized as a dissociative anesthetic. As a non-competitive antagonist of NMDA receptors, ketamine has been widely used in anesthesia and pain management. At low doses (0.5 mg/kg intravenous), ketamine is effective in providing sedation and supplemental analgesia in both local and regional anesthesia techniques.15 Traditionally, clinicians are somewhat hesitant to utilize ketamine because of the associated psychomimetic effects such as: possible agitation, nightmares, out-of-body experiences, nystagmus and visual or auditory illusions. In acute and chronic pain, ketamine has shown effective analgesic properties in the presence and absence of opiates, as well as non-steroidal anti-inflammatory medications.2,16 A number of case reports have described the success of ketamine in pain refractory to standard therapies.17

The current systematic review is intended to determine if using ketamine as an adjuvant to opioid-based therapy in adult patients over the age of 18 years decreases the severity of pain in opioid tolerance more effectively than standard opioid-based therapy. The results will assist healthcare providers in determining if there is sufficient evidence to use ketamine in the perioperative period as an adjuvant therapy to opioid-based therapy in adult opioid-tolerant patients undergoing an orthopedic surgical procedure within the perioperative period.

During the development of this systematic review protocol, a review of the literature on opioid tolerance and ketamine was conducted. One systematic review assessed the effects of intravenous ketamine on postoperative pain, not limited to types of patients or types of surgeries.18 No other systematic reviews or reviews in progress were found in CINAHL, Ovid MEDLINE, Cochrane Library, JBI Database of Systematic Reviews and Implementation Reports, EMBASE and PROSPERO databases.

Inclusion criteria

Types of participants

The current review will consider studies of participants who are:

* 18-70 years old

* Undergoing an orthopedic surgical procedure, specifically hip, knee or spinal surgery

* Opioid-tolerant patients (including OIH).

Different researchers use different equianalgesic measurements to diagnose opioid tolerance. Any study using such measurements to define opioid tolerance is considered for inclusion.

Participants are excluded if they have ischemic heart disease, tachyarrhythmias, uncontrolled hypertension, a history of psychosis or altered mental status and cognitive or memory disorders.

Types of intervention(s)/phenomena of interest

The current review will consider studies that evaluate intravenous ketamine as a perioperative adjuvant to opioid-based pain therapy, compared to opioid-based pain therapy alone.

Outcomes

The current review will consider studies that include the following outcome measure: pain scores as exhibited by single-dimension pain scales. Examples include the Visual Analog Scale, Numeric Rating Scale or Wong-Baker FACES Pain Rating Scale. Secondary outcomes include adverse effects of ketamine, the timing of ketamine administration (induction, intraoperatively and postoperatively), types of opioid-based therapy and administration and pain measurement points (measured in hours post-administration of ketamine).

Types of studies

The current review will consider randomized control trials as the best evidence to answer the question of effectiveness.

Search strategy

The search strategy aims to find both published and unpublished studies. A three-step search strategy will be utilized in this review. An initial limited search of MEDLINE and CINAHL will be undertaken followed by analysis of the text words contained in the title and abstract, and of the index terms used to describe each article. A second search, using all identified keywords and index terms, will then be undertaken across all included databases. Third, the reference list of all identified reports and articles will be searched for additional studies. Only studies published in English or available in English after 1995 to present will be considered for inclusion in this review.

The databases to be searched include: CINAHL, Ovid MEDLINE, SCOPUS, EMBASE and Cochrane Control Register of Clinical Trials.

The search for unpublished studies will include: theses and dissertations, reports, non-independent research or other documents produced and published by governmental agencies, academic institutions and other groups that are not distributed or indexed by commercial publishers; and unpublished scholarly papers. This search will include ProQuest Dissertations and Theses Global and http://www.clinicaltrials.gov.

Assessment of methodological quality

Quantitative papers selected for retrieval will be assessed by two independent reviewers for methodological validity prior to inclusion in the review using standardized critical appraisal instruments from the Joanna Briggs Institute Meta Analysis of Statistics Assessment and Review Instrument (JBI-MAStARI) (Appendix I). Any disagreements that arise between the reviewers will be resolved through discussion or with a third reviewer.

Data extraction

Quantitative data will be extracted from papers included in the review using the standardized data extraction tool from JBI-MAStARI (Appendix II). The data extracted will include specific details about the interventions, populations, study methods and outcomes of significance to the review question and specific objectives. Data will be extracted by primary (MB) and secondary (LB and WK) reviewers independently before discussing or exchanging any opinions to facilitate accurate and reliable data entry. The authors of primary studies will be contacted for missing or unclear data.

Data synthesis

Experimental quantitative study results will be pooled in statistical meta-analysis using JBI-MAStARI. All results will be subject to double data entry. Effect sizes expressed as odds ratios and weighted mean differences and their 95% confidence intervals will be calculated for analysis. Heterogeneity will be assessed statistically using the standard chi-square or I² and also examined via subgroup analysis for adverse effects of ketamine, the timing of ketamine administration (induction, intraoperatively and postoperatively), types of opioid-based therapy and administration and pain measurement points (measured in hours post-administration of ketamine). When statistical pooling is not possible, the findings will be presented in narrative form including tables and figures to aid in data presentation where appropriate.

Observational quantitative papers will be pooled in statistical meta-analysis using JBI-MAStARI. All results will be subject to double data entry. Effect sizes expressed as relative risk for cohort studies, odds ratios for case-control studies and weighted mean differences for continuous data and their 95% confidence intervals will be calculated for analysis. A random effects model will be used and heterogeneity will be assessed statistically using the standard chi-square. Where statistical pooling is not possible, the findings will be presented in narrative form including tables and figures to aid in data presentation where appropriate.

Acknowledgements

Thanks to Mary Marix MLIS for assistance in searching databases for the studies in this review. This review contributes to the Doctor of Nursing Practice degree for William Kuhn.

Appendix I: Appraisal instrument

MAStARI appraisal instrument

Appendix II: Data extraction instrument

MAStARI data extraction instrument

References