Authors

1. Leane, Terrence A RN BEd GDPH MNSc

Abstract

Review question/objective: The objective of this review is to assess whether intravenous fentanyl, of the available analgesia options, has the "best" pharmacokinetic/pharmacodynamic profile for short procedural analgesia, in the setting of intravenous midazolam induced sedation, with or without local analgesia.

Background: Many investigative and therapeutic medical procedures are painful, uncomfortable and/or otherwise distressing to the patient. The International Association for the Study of Pain (IASP) defines pain as "an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage."1^(p.5)

The IASP describes acute pain as being "of recent onset and limited duration". Acute pain usually has an identifiable temporal and causal relationship to injury or disease. The IASP upholds that "pain is not a directly observable or measurable phenomenon, but rather a subjective experience that bears a variable relationship with tissue damage."2^(p.1)

A 'short' painful procedure may be described as an intervention anticipated to take less than 60 minutes, although many procedures generating acute pain can take as little as five to 10 minutes. These short interventions usually involve manipulation of the body in a way that generates pain, such as placement of a needle once or multiple times, placement of a percutaneous catheter or drainage tube, insufflation of the colon with air to facilitate colonoscopy, or bone trephine during bone marrow biopsy.

A number of options are available to help ameliorate the pain, discomfort and distress generated by such experiences, including local anesthesia, general anesthesia or procedural sedation and analgesia (PSA). Equipment and staffing resources required for general anesthesia, local anesthesia and PSA vary substantially and there is potential benefit, both in terms of timely access and economics, to using the most appropriate and 'least complex' anesthesia approach to facilitate a medical procedure.3-5 Many short procedures can be undertaken with PSA.

Whilst superficial diagnostic or surgical interventions may be performed with local anesthesia alone, complete regional anesthesia is often not possible and/or undesirable for many procedures. Some procedures, such as muscle biopsy by needle, specifically require that local anesthesia not be used beyond the skin. Many procedures may be performed with spinal anesthesia or individual limb anesthesia (nerve or Bier's block), but the placement of regional anesthesia is not without risk and often requires a recovery time longer than that for PSA.

PSA is induced through the administration of drugs which produce analgesia, anxiolysis, amnesia, sleepiness and relaxation.6 A number of different terms have been used to describe this approach, including 'conscious sedation', but the depth of sedation and analgesia may vary and the more generic terms 'procedural sedation' or 'procedural sedation and analgesia' have been adopted to describe the wide range of specific sedation and analgesia techniques which may be employed.7,8

A number of guidelines have been published to guide the use of midazolam and fentanyl for PSA.9,10 These guidelines are often written to guide the practice of personnel with no formal training in sedation pharmacology or sedation clinical practice.

Some procedures, such as bone marrow biopsy, are very short, with the discomfort or pain lasting only 2-5 minutes. In 2011, Watmough and Flynn completed a structured evidence review of analgesic approaches for bone marrow biopsy in adults.11 Conducting an extensive literature search, they identified 12 research reports for consideration. Their review found, rather surprisingly, that in spite of the popularity of PSA, no study had examined the analgesic effectiveness of fentanyl for bone marrow biopsy. All of the identified papers described bone marrow biopsy as causing pain, with one research study finding that without sedation or analgesia, 85% of subjects experienced "intense pain".12 Watmough and Flynn's report revealed that most of the identified "pain intervention" strategies were actually a reliance on benzodiazepine-induced sedation and amnesia, as opposed to true analgesia.

A contentious argument is that where a medical procedure is to be a 'one off' event or a 'short' procedure, that it is acceptable that the patient may experience some minor discomfort, or even pain. Or, even if the analgesia is inadequate, any pain that the patient may experience is unlikely to be remembered because of the amnestic effect of midazolam or other drug used for sedation. However, many clients receiving health services, such as hematology or renal medicine, endure repeated painful procedures, such as bone marrow biopsy or balloon arterio-venous fistuloplasty. The discomfort associated with these short, painful procedures is usually brief, but can be very intense and distressing. The amnesia which is associated with benzodiazepine sedation is not guaranteed,13 and patients may be left with the memory of a traumatic experience. Patients may ultimately refuse, or be extremely reluctant to present for a repeat procedure because of the anxiety and distress precipitated by memories of the first painful experience. Getting PSA correctly targeted for each individual patient is an important clinical step, which improves the quality of the patient's overall experience with the health service and ultimately builds trust between the patient and the clinician, facilitating improved compliance with disease management.

Kost14^(p.99) has identified the ideal characteristics (pharmacokinetics/pharmacodynamics) of injected drugs for PSA to include:

* Rapid onset of action

* Short duration of action

* Lack of cumulative effects

* Rapid recovery

* Minimal side effects

* Rapid metabolism to inactive non-toxic metabolites

* Residual analgesia

No single drug satisfies all of the requirements for PSA or meets all of the identified ideal characteristics. A combination of drugs is usually required, but many drugs will provide multiple effects; for example droperidol is both anti-emetic and sedative. The sedationist is faced with a choice of multiple agents for both the sedation and analgesia components of PSA and must consider the combined and possibly synergistic effects of the drugs chosen.15,16

Over the past half century, a number of drugs have come into and gone out of favor for PSA, but outside of anesthesia and emergency room environments, the most commonly used drugs to facilitate PSA in adults are now perhaps the short-acting benzodiazepine midazolam and the opioid fentanyl, both given intravenously.17 These drugs have been in common use for the past 25 years.

The drug propofol is a general anesthetic induction and maintenance agent, which is also an excellent hypnotic sedative. It is in common use for procedural sedation and although its analgesic properties appear to be limited,18 using propofol for procedural sedation can reduce or even eliminate the requirement for an opioid analgesic. In the hands of a competent and trained sedationist, propofol is a safe and effective drug. However, it has a narrow margin of safety and can rapidly induce deep unconsciousness and loss of airway. Its use by non-anesthetists is controversial and not accepted in all settings.19 The use of midazolam-based PSA therefore remains necessary and widely practiced.

In a controlled setting, the administration of midazolam and fentanyl for PSA is generally considered safe and effective for many procedures and may be performed by a non-anesthetist sedationist.20 Although midazolam may exhibit some analgesic qualities when used in combination with local anesthesia for regional block, systemic analgesia is likely very limited.21 The evidence is somewhat contradictory, but sedative-hypnotic drugs may actually increase pain perception. It is generally accepted that when sedation is induced for a painful medical procedure, supplementary analgesia should be used.22

Apart from fentanyl, other analgesic drugs have been used for procedural analgesia, including (but not limited to) oxycodone, morphine, meperidine (pethidine), alfentanil, sufentanil and remifentanil. Some of these agents may be delivered through methods other than the intravenous route. Each analgesic option presents the sedationist with perceived advantages and disadvantages, including onset and analgesia effect times, depth of analgesia, safety and side-effects.23 Anesthesia and sedation practice are often described as both a science and an art. The training, knowledge and experience of the sedationist inform the decision making involved in developing a PSA plan for each individual patient and procedure, including choice of sedation and analgesic agents.

Fentanyl is a synthetic opioid first isolated by Dr. Paul Janssen in 1960.24 It has a relatively short onset and elimination time, is associated with few unpleasant side-effects and has a relatively good margin of safety.20,25 Because of this pharmacological profile, intravenous fentanyl is commonly used for procedural analgesia.26

However, the necessity, utility and safety of fentanyl, when used for short PSA, are not clear. Among anesthesia/sedation providers, PSA practices for short painful procedures do vary widely and each anesthetist/sedationist is able to give reasoned justifications for his or her own approach. A systematic review of the existing research related to the effectiveness and safety of fentanyl can be used to inform clinician decision making about selection of analgesia for short, painful procedures and assist in the future development of guidelines for the use of fentanyl or other analgesic approaches during PSA.