Conference Lectures

PATIENT CONTROLLED ANALGESIA
Dr. V.P. Kumra, MD, DA, D Ac, MAc.FI, FICA
President, Indian College of Anaesthesiologists, Emeritus Consultant
Department of Anaesthesiology, Pain and Perioperative Medicine,
Sir Ganga Ram Hospital, New Delhi-110 060

Patient controlled analgesia represents an optimal mode of administration of an analgesic agent to provide constant pain relief in the surgical patient during the postoperative period. The concept is based on various factors: the traditional approach of intramuscular (IM) opioids given on Pro Re Nata (PRN) results in 50% of patients experiencing inadequate pain relief after surgery; Novel bioengineering and new technology have come out with more sophisticated, safe, “user friendly” infusion devices; improvement in postoperative analgesia reduces the morbidity and hospital stay of surgical patients leading to cost containment, that suits the hospital administrators and insurance companies. These reasons now stand permanently to replace old traditional approach of IM, or oral pain relief methods. So it must be realized that PCA is a conceptual framework for the administration of analgesics given by any route of delivery (i.e. oral, subcutaneous, epidural, intravenous, peripheral nerve catheter etc).
Historically, Marks and Sachar’s landmark publication (1973) ignited a revolution for the adequacy of conventional analgesic practice. It highlighted the under treatment of surgical patients, misconception of physicians and nurses regarding the effective use of opioids and finally led to the search for the perfect mode of administration and delivery system. Regular improvements in technology led to the development of first commercially available PCA pump (1973), the “Cardiff Palliator.” Since then, PCA devices have evolved sophistication continuously.

THE PCA PARADIGM

 Opioid analgesia is achieved when the plasma concentrations reach a specific effective level for an individual. Any increase in plasma concentration leads to a rapid decrease in appreciation of pain. The nadir for the perceived pain defines the minimal effective analgesic concentration (MEAC) (Figure 1). Concentration above MEAC there is no further increase in intensity of analgesia and any decrease in plasma concentration, there is rapid                                                           
 appreciation of pain. There is considerable interpatient variability for MEAC, explaining the different dose requirement in different individuals. Continuous intravenous administration of opioids improves the controllability of pain, avoiding the peaks and troughs (Figure 2). As the postoperative pain decreases with time, the requirement for analgesics too decreases. PCA modality can help unnecessary over dozing of the opioid analgesia. It allows on- demand, repetitive dosing of small amount of opioids with the fall in plasma concentration below the MEAC i.e. PCA allows the patient to titrate their plasma concentration of opioids around MEAC thus a more consistent analgesia.
PCA Modes and Dosing Variables
 Two common modes of administration are demand dosing (a fixed size dose administered as required) and continuous infusion plus demand dosing (a fixed back-ground infusion supplemented by patient dosing). Some PCA devices also have programmed infusion demands and preprogrammed variable-rate infusion plus demand dosing (Figure 3)
All PCA modes are having the basic variables: initial loading dose (allows for initial titration of medication by the doctor or nurses), demand dose (allows the patient to top up a fixed dose of analgesic), lockout interval (a safety device to prevent unnecessary dosing by repetitive pressing of demand  button), background infusion rate (a continuous infusion is a constant rate infusion administered irrespective of demand) and 1-hour and 4-hour limits (to minimize cumulative dosing after the lockout time). At the same time, it can also be interpreted that if the patient reaches the 1-hour or 4-hour limits that they require more analgesic instead of being locked out from further access for the balance of the interval. Most modern microprocessors PCA devices allow parameters in units of µg, mg or mL units. This will reduce the potential for programming errors when using fentanyl or sufentanil for extremes of ages even. The demand dose should be enough to produce appreciable analgesia with a single dose. There is an optimal safe range of doses for each period that will avoid under or toxic dose for an individual, who needs pain relief. Lockout period is designed to prevent overdosing and should be long enough for the patient to experience good pain relief with a single dose. Speed of onset is thus most important, therefore, slightly shorter lockout period is selected for shorter acting drug like fentanyl or sufentanil than morphine. Owen et al suggested that rate of drug distribution (flux) between plasma and brain is a useful concept in determining the lockout interval. The subsequent dose should be administered when the flux becomes negative i.e. when the drug is leaving the brain and the effect has peaked.
The relative onset time for the opioid to act varies with the different opioids (1 min for alfentanil to 6 mins for morphine) and relative duration of action (2 min to 96 min respectively). All the commonly   used opioids except alfentanil are suitable for IV – PCA. Furthermore, titration is improved by frequent administration of small doses after initial “loading” period. Thus there is a pharmacokinetic rationale for the empirically derived use of 12 - min lockout period for the opioids commonly used for IV – PCA.

CLINICAL MANAGEMENT
Choice of opioids
Commonly used opioids for IV – PCA, are those acting on µ - receptors and can be classified as:
Pure agonists (Morphine, Fentanyl, Hydrmorphone, Meperidine, Sufentanil, Alfentanil, Remifentanil); Agonists – antiagonists: (Butorphanol, Nalbuphine, Pentazocine); Partial agonists (Buprenorphine, Dezocine). Whichever opioid is selected for IV-PCA, anaesthesiologists must possess full knowledge of its pharmacology. The regimens for the commonly used opioids for IV-PCA are (Table 1):            

Opioid	Concentration	Demand dose	Lockout time	Continuous basal
Morphine	1-mg /mL	1 -2 mg	6 – 10 min	0 – 2 mg / hr
Hydromorphone	0.2 mg / mL	0.2 – 0.4 mg	6 – 10 min	0 – 0.4 mg / hr
Fentanyl	10 µg / mL	20 – 50 µg	5 – 10 min	0 – 60 µg / hr
Sufentanil	2 µg / mL	4 -6 µg	5 – 10 min	0 – 8 µg / hr
Meperidine	10 mg / mL	10 – 20  mg	6– 10 min	0 – 20 mg / hr
Tramadol	5 mg/mL	10 – 20  mg	6– 10 min	0 – 20 mg / hr

The pure agonists are mainstay of acute pain management because they provide full µ binding, i.e. there is no analgesic ceiling and titration of more opioid results in better pain relief. However, there is a clinical ceiling because of the side effects like sedation, respiratory depression etc.
The agonist–antagonist opioids provide k–receptor activation and µ-receptor antagonism. They possess ceiling effect on both respiratory depression and analgesic effect, rendering them unable to reliably provide a level of pain relief comparable to µ-agonists. In addition these drugs can have acute withdrawl response specially those maintained on µ - receptor agonists. So agonist–antagonists are not commonly used as IV-PCA and morphine remains the “gold standard”   for IV- PCA in clinical practice.

INITIAL DOSING AND MAINTENANCE REGIMEN
It is always better to start with an equipotent dose of an opioid (1 mg of morphine,                       0.2mg hydromrphone, 20 – 30 µg fentanyl) with 6-8 min lockout interval in opioid - naïve patient. Initial loading dose of morphine or fentanyl is administered in post anaesthesia care unit (PACU) every 5-10 min until the pain score is < 4 of 10 or a respiratory rate of < 12 breaths / min. If the patient complains of pain, a bolus dose is given and the demand dose is increased, after confirming that patient is pushing the button adequately. No continuous basal infusion is started till the patient’s pain is increasing, rather it is better to add non–opioid analgesic or multimodal analgesic.
The commonly observed side effects with opioid administration are sedation, nausea and vomiting, pruritis, confusion and less commonly respiratory depression. Post operative nausea and vomiting (PONV) are the most common and bothersome side effects, therefore strategies to reduce PCA – PONV associated with IV-PCA should be observed according to “The Consensus Guidelines for managing PONV” that promotes risk stratification approach. Various drugs have been tried but the Consensus Guidelines recommend the use of single – drug prophylaxis for patients with mild to moderate risk, combination prophylaxis with Droperidol plus a serotonin antagonist  or dexamethasone for patients with moderate to severe pain. For patients with very high risk, a combination of antiemetic plus consideration for total IV anaesthesia with Propofol or regional anaesthesia is recommended. Various drugs recommended are droperidol, ondansetron, dexamethasone, continuous infusion of subhypnotic doses of propofol, transdermal scopolamine and promethazine.
IV-PCA related pruritis are effectively treated with diphenhydramine (12.5–25.0 mg IV, hydroxyzine 50 mg IM  and alizapride 50 mg IV ).
Sedation and confusion may be noticed in patients receiving morphine lesser with fentanyl specially those with deranged renal functions, because of accumulation of morphine active metabolites. Co-administration of round the clock Non-steroid anti inflammatory drugs (NSAIDs) reduce the incidence of sedation.

Postoperative confusion or delirium in elderly patients will need prophylaxis and management of the causative factors. Established cases of delirium require good nursing care or managed pharmacologically with Haloperidol orally /  IM or  Dexmeditomidine ( 0.1 – 0.4 mcg per kg  per hour.       

SAFETY ISSUES ASSOCIATED WITH PCA
PCA by Proxy:  When individuals other than the patient push PCA button, they may seriously misjudge the patient’s level of sedation, resulting in extreme over-sedation and respiratory depression.   

Patient factors: Although the age has no significant affect on PCA administration, the dose demand for analgesics decreases with age so lower dosages should be used. Patients must be cognitively, physically and psychologically capable of understanding the concepts of PCA and handling the device necessary to obtain pain relief. Patients with morbid obesity, asthma or sleep apnoea or those on concurrent therapy that potentiate opioids are not good candidates for PCA. Opioid –tolerant patients ( illegal consumers or addicts ) may have to be given higher dosages or increased basal concentrations to fulfill their daily demands. Positive aspects about PCA is that in addition to instant pain relief, patients can avoid injection and have not to bother the nursing staff, who can be spared to look after serious patients.

Patient monitoring: Inadequate patient assessment and monitoring of patients using PCA remains a source of potential error. Pain management team should develop a standard sedation scale, risk factors to predict respiratory depression in patients on PCA that can be used for assessment and monitoring and documenting the level of sedation for their institution.

Medical and nursing staff factors:Operator errors during programming of incorrect bolus dose, drug concentration, background infusion etc can result into over sedation or respiratory depression. So each institution must standardize the drug concentration to reduce such mishaps. The programmed schedule must be checked by the senior pain therapist. The medical and nursing staff must possess adequate knowledge to operate the PCA device.

Patient education: Patients who are candidate for post-surgical use of PCA and their relative / attendant must be taught preoperatively, the relation between pain, pushing the button and adequate pain relief, benefits of PCA and its working procedure.

Psychological characteristics: Subjective experience of pain depends on anxiety, neuroticism and coping style. These characteristics may affect how well patients make use of PCA and, therefore, its effectiveness should be taken into account when patients are considered for PCA.    

Background infusion: Whereas the routine addition of background infusion has not been shown to be more advantageous for pain relief in the postoperative period. It has been reported to be responsible for respiratory depression specially in women undergoing abdominal hysterectomy during night time continuous basal infusion.

Limitations of IV-PCA: Although IV-PCA has a very acceptable safety profile, life threatening complications do occur. It does not reduce any morbidity or mortality except slight reduction in pulmonary complications. Moreover it is definitely inferior to postoperative continuous epidural analgesia (PCEA) and other peripheral continuous nerve blocks. IV-PCA also may impede postoperative mobilization.

Cost-effectiveness analysis of IV-PCA: Choiniere M, Rittenhouse BE et al in their study concluded that IV-PCA is more expensive than IM injections, despite PCA pump cost being excluded. However, one must place the cost of providing IV-PCA or epidural analgesia into overall perspective of health care cost. Other factors considered in a cost analysis of PCA therapy are: (cost of PCA pump, the drug, and the disposables, nursing time, and the hidden cost like: storage and inventory management, transport,  distribution and maintenance cost).

Strategies to improve efficacy of opioid IV-PCA: IV-PCA should not be considered the only and the best mode of postoperative pain management. Benefits of Multimodal approach to acute pain  relief must be considered (a round the clock NSAIDs administration, local wound infiltration, peripheral nerve blocks and continuous catheter techniques). Mixture of drugs used may be better than one drug alone as it will reduce the side effects of a single drug and at the same time provide better pain management results.

ALTERNATIVE ROUTES OF PCA DELIVERY
The concept of PCA is to supply an analgesic round the clock to provide postoperative pain relief in surgical patients. Alternative routes of PCA delivery like Epidural PCA (PCEA); Peripheral nerve catheter PCA (perineural and incisional catheter techniques); Transdermal PCA (non invasive method of PCA, Iontophoretic delivered ionizable drugs), oral and nasal sufentanil drops must be considered.

FUTURE DIRECTIONS OF PCA DEVELOPMENTS
Novel routes of PCA delivery will continue to evolve and become a common use in postoperative pain management. The improvement desired is specially in the capability of eliminating programmable drug concentrations and capability to customize rate and dosing limit variables. Patient controlled regional analgesia (PCRA) is definitely going to be more commonly used as the anaesthesiologists gain proficiency in regional anaesthesia. Transdermal iontophoretic delivery also holds much promise for simplified preprogrammed opioid delivery and different doses can be administered as desired.  

CONCLUSION
Patient controlled analgesia is a process to provide pain relief to surgical patients by disposable or electronic infusion devices. It is very effective and safe method of pain relief and allows the patient to titrate the dosages according to their needs. However, it is not “one set fit all” therapy. The safety measures as mentioned must be followed in order to avoid accidents. It is then the popularity of PCA will continue and will remain a regular by used method for pain relief. Other methods of continuous pain relief like PCRA, PCEA must be given priority as and when suitable.

Suggested Reading

1. Ferrnte FM. Patient controlled analgesia. Anesth Clin North Am 1992;10(2):287-98.
2. Grass JA. Patient-controlled analgesia. Anesth Analg 2005; 101(5 Suppl):S44-61.
3. Sachzer PH. Objective measurement of pain. Anesthesiology 1968; 29: 209-10.
4. Gan TJ, Meyer T, Apfel CC, et al. Consensus guidelines for managing postoperative nausea and vomiting. Anesth Analg 2003; 97: 62-71.
5. Choiniere M, Rittenhouse BE, Perrealt S, et al. Efficacy and cost of patient controlled analgesia versus regularly administered intramuscular opioid therapy. Anesthesiology 1998; 89:377-88.
6. Macintyre PE. Safety and efficacy of patient-controlled analgesia. Br J Anaesth 2001; 87(1): 36-46.
7. lubenow TR, IVankovich AD, Barkin Rl. Management of Acute postoperative pain. In Clinical Anaesthesia. Barash PG, Cullen BF, Stoelting RK (Eds) 5th Edition. Lippincott Williams and Wilkins 2006; Chapter 55: page 1405-1470.