The Effect of Perioperative Ketamine on Acute and Chronic Pain After Major Back Surgery
Information source: University Hospital, Geneva
ClinicalTrials.gov processed this data on August 23, 2015 Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Postoperative Pain
Intervention: Placebo (Drug); Ketamine (Drug)
Phase: Phase 2
Status: Completed
Sponsored by: University Hospital, Geneva Official(s) and/or principal investigator(s): Martin Tramèr, Prof, MD, PhD, Study Chair, Affiliation: anesthesia department Christoph A Czarnetzki, MD, MBA, Principal Investigator, Affiliation: anesthesia department
Summary
After a surgical operation, patients may suffer from chronic pain. Ketamine, a well known
anesthetic acts on receptors in the spine (NMDA receptors), which are implied in the
occurrence of chronic pain. The mechanism is called central sensation. It is known that
Ketamine reduces immediate postoperative pain, but its effectiveness in the prevention of
the chronic pain is still unknown. The investigators study will follow patients until one
year after operation for the occurrence of chronic pain. The investigators hypothesis is
that Ketamine reduces significantly chronic postoperative pain after major back surgery and
improves patient outcome.
There may be important inter-individual differences how persons react on a drug. These
differences are partly determined by the genes of each individual. The investigators study
includes therefore a genetic analysis.
Psychological and social factors also influence the perception of pain. It is still not well
understood who these "psychosocial factors" determine the appearance and perception of
chronic pain. In the investigators study the investigators will therefore study these
factors by questionnaires.
Clinical Details
Official title: The Effect of Perioperative Intravenous Low-dose Ketamine on Acute and Chronic Neuropathic Pain After Major Back Surgery. A Randomised, Placebo-controlled, Double-blind Study
Study design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Prevention
Primary outcome: To evaluate the long-term (6 and 12 months) effect of perioperative intravenous low-dose ketamine on chronic neuropathic pain in patients undergoing major back surgery.
Secondary outcome: To evaluate the short-term (during hospitalisation) effect of perioperative intravenous low-dose ketamine in patients undergoing major back surgery: tolerability and safety, opioid-sparing effect, pain intensity, morphine-related adverse effects.To study the potential impact of genetic variability of several enzymes (CYP2D6, CYP2C9, COMT) known to modulate pain sensitivity and/or metabolism of opioid and NSAIDs on analgesic consumption and ketamine response. To study psychosocial factors that may be involved in the perception of acute and chronic postoperative pain in patients with or without chronic back pain undergoing back surgery. To study the pharmakokinetics of an intravenous low-dose ketamine infusion.
Detailed description:
Background
1. Ketamine as an adjuvant to multimodal postoperative analgesia and its impact on the
development of chronic neuropathic pain:
Ketamine, a phenylcyclidine derivate, was developed in the 1960's to be used as a
general anesthetic. The pharmacological mechanism of ketamine remained unclear for a
long time. However, more recently, the antagonistic role of ketamine at the
N-methyl-D-aspartate (NMDA) receptor was identified. Consequently, it has been
suggested that ketamine should be used as an adjuvant for multimodal pain treatment.
During the last 15 years, a large number of clinical trials have been published that
tested ketamine for the management of acute postoperative pain. Three meta-analyses
have confirmed an opioid sparing effect in the immediate postoperative period, a
decrease in post-operative pain intensity, and an increase in the delay until the first
request of rescue analgesia in patients who were randomised to intraoperative ketamine
[Elia & Tramèr, 2005; Bell et al, 2005; Himmelseher & Durieux, 2005]. There was no
evidence of an increase in the incidence of nightmares or unpleasant dreams when
patients received low-dose ketamine as an adjuvant to a general anesthetic [Elia &
Tramèr, 2005].
Additionally to these short-term perioperative effects, ketamine is supposed to reduce
the development of chronic neuropathic postoperative pain through NMDA receptor
blockade and a reduction of wind-up and central sensitization [Woolf 2000]. Chronic
postoperative pain is a major source of morbidity [Perkins & Kehlet, 2000]. Certain
types of surgery, such as breast surgery, thoracotomy, inguinal hernia repair and limb
amputation are considered as "high risk" interventions for developing neuropathic pain.
After thoracotomy, for instance, incidences of chronic neuropathic pain up to 60% have
been reported. A few studies only have looked at long-term outcomes. In a small pilot
study, a beneficial effect of ketamine on persistent painful sensations around the scar
was observed for up to 6 months after surgery [De Kock et al, 2001]. Chronic
neuropathic pain remains an important therapeutic challenge. The pathophysiology of
neuropathic pain has shown that central sensitisation might play an important role
through hyperactivity/ hyperexcitability of spinal/supraspinal nociceptive neurons.
Ketamine, which modulates NMDA receptors, is known to reduce neuropathic pain and might
even prevent it. Furthermore, opioid resistance of neuropathic pain is a common feature
and thermal sensory deficits within the painful area are predictive of the intensity of
opioid response.
In order to improve our understanding of the frequently observed variability in the
response rate to ketamine, and to describe in more details the low back pain cohort we
intend to study, we will address two further issues; first, pharmacogenetics of
ketamine, and second, psychosocial factors that may influence the perception of
postoperative pain and may predict the response to ketamine in patients with or without
chronic low back pain.
2. Pharmacogenetics of ketamine:
Factors that can affect the individual response to drugs are genetic and non-genetic,
as for instance, compliance, age, body fat, nutrition, concomitant disease (such as
liver and kidney diseases), and drugs or toxic substances (such as tobacco, alcohol,
and environmental pollutants). The individual response to a drug is influenced by the
combination of pharmacokinetic (absorption, distribution, metabolism, excretion) and
pharmacodynamic processes. Each of these processes, as well as the underlying
pathological painful condition, involves genetic and environmental factors that can
affect the response to an analgesic. The only consistent and predictable factor might
possibly be the genetic one, and thus pharmacogenetics may help individualizing drug
treatment in accordance with the genetic "make-up" of the patient. Pharmacogenetic
tests are now available in clinical practice and might help to better identify the best
analgesic and also to estimate the optimal dose for an individual patient. Finally,
this genetic knowledge should lead to mechanism-based approaches for the discovery of
new analgesics.
Polymorphic drug metabolizing enzymes and drug transporters affect the pharmacokinetics
of drugs whereas polymorphic drug targets and disease related pathways influence the
pharmacodynamic action of drugs [Samer et al, 2006]. Prospective trials are urgently
needed to study the inherited susceptibility that may lead to a lack of therapeutic
analgesic efficacy, or dose-dependent induced adverse drug reactions.
We choose high-priority candidate polymorphisms that we predicted would be associated
with pain-related response or resistance to post-operative pain treatment. CYP2C9,
CYP3A4, CYP2D6 are alleles involved in the metabolism of analgesics such as
non-steroidal anti-inflammatory drugs (NSAID), ketamine, tramadol, or ondansetron (for
review, see [Samer et al, 2006]). As for pain sensitivity and morphine response
variability, the met allele at the val158met polymorphisms in the
catechol-O-methyltransferase gene (COMT), reduces the ability of the enzyme to
metabolize catecholamines, and has been associated with a decrease in opioid
consumption in cancer pain patients. Furthermore, COMT polymorphisms interacts with the
nociceptive and emotional system since the variability in experimentally evoked pain
thresholds is linked to this genetic polymorphisms [Zubieta et al, 2003]. Unpleasant
pain-related affect, and anxiety disorders have also been associated with this
polymorphisms [Olsson et al, 2005]. The met allele has been associated with depression
and anxious temperament; both are well known risk factors for developing chronic pain
[Hwang et al, 2005]. In addition to the a priori selection of these putative genes, we
will carry out exploratory analyzes of polymorphisms in some additional genes that we
had previously genotype for pain genetics studies. We recognize that correction for
multiple testing might need a cohort of several hundred patients; thus, our
observations and analyzes may be suitable only for generating hypotheses for future
studies.
3. Psychosocial factors of pain perception in patients with back pain undergoing surgery:
Pain intensity is strongly associated with disability. Aside the importance of symptoms,
function, general well-being, work status, and satisfaction with care have been proposed as
a core set of outcomes in clinical trials and routine care settings [Mannion et al, 2005].
Psychological distress and depressive mood increase the risk of chronicity. A systematic
review evaluated psychological predictors of chronicity and disability in prospective
cohorts of low back pain patients [Pincus et al, 2002]. Increased risk of chronicity (i. e.
persisting symptoms and/or disability) as a result of psychological distress and depressive
mood emerged as the main finding.
Patients' beliefs and expectations about their pain problem also seem to influence the
recovery process. Patients' expectations about treatment have been shown to influence the
outcome, i. e. functional improvement, for example, can be linked not only to the intrinsical
value of treatment but also to the patients' expectations of its possible benefits. Lutz et
al showed that patients with higher expectations of surgery had better outcomes than those
with lower expectations [Lutz et al, 1999]. Iversen et al found that patients with many
preoperative expectations tended to improve more than those with fewer expectations [Iversen
et al, 1998]. More ambitious expectations for physical function were also associated with
improved function and satisfaction with physical function; however, high expectations for
pain relief were associated with greater report of pain and decreased satisfaction with pain
relief, thus suggesting that these types of expectations should be addressed differently in
preoperative discussions.
Investigating the relationship between expected results and actual outcomes, McGregor &
Hughes assessed patients' expectations of surgery, and satisfaction with outcome in terms of
pain, function, disability and general health at 6 weeks, 6 months and 1 year [McGregor &
Hughes, 2002]. The results showed that patients had high expectations of recovery and were
confident of achieving this recovery. As for satisfaction, however, patients' reports at all
review stages indicated that surgery had achieved only part of what they had expected,
suggesting that patients had unrealistic expectations leading to lower satisfaction levels.
Painful experiences may be accompanied by catastrophizing cognitions, i. e. pessimistic
beliefs and expectations regarding the self, the others and the future, which may give rise
to feelings of helplessness concerning one's ability to cope with life events. This may lead
to pain-related fear, avoidance behaviors, and to reduced activity. Disability and disuse
may ensue and be associated with depression, thus increasing pain and catastrophizing and
setting into motion a vicious circle. When back pain is not associated with catastrophizing
thoughts, the absence of fear allows for the confrontation with activity and eventually for
recovery [Vlaeyen & Linton, 2000]. This model refers to both cognitive factors (e. g. meaning
of pain, expectations regarding control over pain, maladaptive thoughts) and behavioural
responses that may be active (e. g. carrying on with daily activities, exercising) or passive
(e. g. rest, giving up control, withdrawal from activities) [Picavet et al, 2002].
Eligibility
Minimum age: 18 Years.
Maximum age: N/A.
Gender(s): Both.
Criteria:
Inclusion Criteria:
- Adults, age ≥18 years, male or female
- American Society of Anaesthesiology (ASA) status I-III.
- Back surgery: laminectomy, lumbar arthrodesis (Posterior Lumbar Interbody Fusion -
PLIF, Transforaminal Lumbar Interboby Fusion - TLIF, Postero-lateral Fusion,
semi-rigid fixation).
- Subjects who have signed and dated an informed consent to participate in the study
during the pre-operative assessment.
Exclusion Criteria:
- Coronary heart disease (unstable angina, MI within the last 6 months)
- Glaucoma.
- History of allergy or hypersensitivity to ketamine or morphine.
- Dementia or inability to understand the study protocol.
- Subjects who have taken any investigational drug or used an experimental medical
device within 30 days before the start of the study or are currently enrolled in
another investigational drug study.
- Failed back surgery syndrome (i. e. an unfavourable condition of a patient following
back or spine surgery).
- Posttraumatic paraplegia.
Locations and Contacts
University Hospital of Geneva, Geneva, Canton of Geneva 1211, Switzerland
Additional Information
Starting date: October 2007
Last updated: April 12, 2013
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