Pain Management

Sunita Goel
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Analgesic Ladder Approach
An analgesic ladder approach to the selection of analgesic drugs for cancer pain has been developed by the CANCER PAIN RELIEF AND PALLIATIVE CARE PROBLEM OF WHO (1996). Patients with mild to moderate pain are usually first treated with acetaminophen or NSAIDS. This drug is combined with one or more adjuvants if a specific indication for one exists. These adjuvants drugs include drugs selected to treat a side effect of the analgesic (e.g. laxatives) and drugs with analgesic effects.

The role of morphine in the management of chronic pain has also evolved with recognition of its active metabolites.

Based on clinical experience, there are a few guidelines for the selection of an opioid as an alternative to morphine. Patients with severe pain, who require rapid dose titration, are generally best treated with drugs that approach steady state after treatment is initiated or the dose is changed. Controlled - release drugs, including the long-lasting morphine and oxycodone preparations and the transdermal fentanyl system, can require up to several days to approach steady-state concentrations and are usually not preferred in this setting.


Pain Management


NSAIDS, Acetaminophen: useful for bone pain, soft tissue pain, dysmenorrhea. May be added at step one and continued on all 3 steps of the ladder.

Effective for most pain types, may require higher doses for neuropathic pain. Add weaker opioid or lower doses of stronger opioids (morphine) at step two of the ladder, increase dose if pain persists or progresses to severe intensity.

Opioid Analgesics (Table 1)

Opioid analgesics used for Rx of chronic pain

Equianal
gesic doses
½ life (hr)Peak effect (hr)Dura
tion (hr)
ToxicityComments
Morphine10 IM, 20-60 PO2-3
2-3
0.5-1
1.5-2
3-6
4-7
Constipation,
nausea,
sedation,
most common
is respiratory depression
(rare in cancer patients)
Standard compound 
for opioids;
multiple routes
available
Controlled release morphine20-60 PO2-33-48-12 
Sustained release morphine20-60 PO2-34-6

Once a day
morphine
Hydromor
phone
1.5 IM, 7.5 PO2-3
2-3
0.5-1
1-2
3-4
3-4
Same as
morphine
Combined
with aspirin as
acetaminophen
for moderate
pain; available
orally with
co-analgesic for
severe pain
Oxymor
phone
1 IM 10 PO--0.5-1
1.5-3
3-6
4-6
Same as
morphine
No oral
formulation
Meperidine75 IM
300 PO
2-3
2-3
0.5-1
1-2
3-4
3-6
Same as
morphine +
CNS
excitation; contraindicated in those on
MAO inhibitors
Not preferred
for cancer due
to potential
toxicity
Heroin5 IM0.50.5-14-5Same as
morphine
Analgesic action
due to
metabolites-
predominantly morphine
Levorpha
nol
2 IM
4 PO
12-150.5-13-6Same as
morphine
Long ½ life
-accumulation
occurs after
beginning or
increasing
dose
Methadone10 IM
20 PO
12- >1500.5-1.54-8Same as
morphine
Risk of delayed
toxicity due to
accumulation;
useful to start
dosing on P.V.N
basis, with close
monitoring
Codeine130 IM
200 PO
2-31.5 - 23-6Same as
morphine
Usually combined with
non-opioid
Propoxy
phene HCl.
-121.5-23-6Same as
morphine + seizures with
overdose
Toxic metabolite
accumulates but
not significant
as doses used
clinically; often
combined with
non-opioid
Propoxy
phene naprylate
-121.5-23-6Same as
Hydrochloride
Same as HCl
Hydro
codeine
-2-40.5-13-4Same as
Hydrochloride
Only available
combined with
acetaminophen
Dehydro
codeine
-2-40.5-13-4Same as
Hydrochloride
Only available 
combined with
acetaminophen
Fentanyl-7-12--Same as
morphine

Fentanyl trans
dermal system
- 6-24-48-72


Route of administration
The oral route for opioid delivery is effective, economical and acceptable to most patients. It is preferred for chronic opioid therapy. During the course of a medical illness, however a substantial proportion of patients require an alternative route, at least for a period of time. A large number of alternative route are available and in the absence of comparative trial, the selection of one or another is based on clinical judgement and experience.

Routes of administration: (Table 2)


RouteComment
OralPreferred in cancer patients
SublingualBuprenorphine effective, efficacy of highly lipid soluble drugs, such as fentanyl is likely but no studies & very little clinical experience. Efficacy of morphine controversial
RectalAvailable for morphine, oxymorphine & hydromorphone. Methadone has been compounded and used successfully.
TransdermalAvailable for fentanyl. Dosing interval is 2-3 days. Empirical indications include difficulty with swallowing or GIT absorption, desire for fentanyl trial, compliance problems with anal dosing, possibly severe constipation and possibly desire to offer an alternative that the patient perceives may improve quality & life
Oral transmucosalFormulations using fentanyl
Subcutaneous:
  • Repetitive bolus

  • Continuous infusion 

  • Continuous infusion with PCA

Ambulatory infusion pumps can provide continuous infusion with any parenteral opioid formulations. Clearest indication is inability to tolerate oral route .
Intravenous:
  • Repetitive bolus

  • Continuous infusion 

  • Continuous infusion with
    PCA

Continuous infusion possible
Epidural: 
  • Repetitive bolus

  • Continuous infusion using
    percutaneous
    or unplanted
    system 

Clearest indication is pain below the mid-chest & Rx limiting Side effects from systemic opioids. Often co-administered with local anesthetics


Tricyclics antidepressants, anticonvulsants, corticosteroids, local anesthetics. Effective for neuropathic pain, may be added at step 1 and continued on all 3 rings of the ladder.

Adjuvant analgesics: The WHO "analgesic Ladder" approach recommends co-administration of adjuvant drugs to treat opioid side-effects or symptoms associated with pain, or enhance analgesia (WHO 1996). This category includes numerous drugs that have primary indications other than pain but are analgesics in specific circumstances.

Adjuvant Analgesics: (Table 3)


IndicationDrugs
Multipurpose drugsCorticosteroids
  • Dexamethasone

  • Prednisone 

Antidepressants TCA
  • Amitriptyline

  • Desi Prome 

Newer anti-depressants
  • Fluoxetine

  • Paroxetine 

Alpha-2 adrenergic agents
  • Clonidine

  • Tizanidine
Neuropathic painNMDA receptor antagonist
  • Ketamine

  • Dextromethorphan 

Anticonvulsant
  • Gabapentin,
    carbamazepine,
    phenytoin,
    valproate,
    Clonazepam,
    Lamotrigine
Oral LA
  • Mexiletine,tocainide

Neuroleptics
  • Pimozide

Miscellaneous
  • Baclofen,calcitonin
Drugs used for
complex regional
pain syndrome
(CRPS)
  • Calcitonin

  • Clonidine 

  • Prazosin 

  • Phenoxy 

  • Benzamine 

Topical agents
  • Capsaicin

  • Local anaesthetics
Drugs for bone
pains
  • Bisphosphonates

  • Calcitonin 

  • Radio pharmaceuticals
Drugs for bowel
obstruction

  • Scopolamine

  • Glycopyrrolate 

  • Octreotide 


Encapsulation Matrices: The action of rapidly cleared drugs can be prolonged by incorporating them in a variety of encapsulation matrices including liposomes, iophendylate and polyanhydride polysomes.

Liposomes: Liposomes are reservoirs containing an aqueous phase surrounded by phospholipid bilayers. Liposomes encapsulation permits the delivery of relatively large concentrations of a drug in the form that is sequestered and slowly released into the local biophase. This exposes the local tissues to relatively steady state concentration of the drug over an extended period by reducing the bio-availability, so high dose effects (respiratory depression) or high dose tissue toxicity may be reduced.

Iophendylate: In rabbits, placing LA in iophendylate prolongs their spinal action.

Transfersomes: A new type of analgesic drug carriers the transfersome, can penetrate rapidly down hydration gradient through the intact dermis and reach cutis and subcutis, thus affecting the nociceptors and mainly vesicular patches. Each transfersomes consists of atleast one inner aqueous compartment. This is surrounded by a lipid bilayer. Transfersomal drug carriers can accommodate hydrophilic drugs or lipophilic drugs.

Microspheres: Encapsulating bupivacaine in poly (D,L)-lactide-co-glycolide microspheres prolongs analgesia and diminishes systemic toxicity.

Spinal implants: Drug delivery systems can be categorized as follows:
- Percutaneously inserted epidural catheters
- Subcutaneously tunnelled epidural/ intrathecal catheter
- Implanted epidural or intrathecal catheter connected to access ports
- Implanted intrathecal manual pumps
- Implanted intrathecal or epidural infusion pumps
- External pumps

During patient selection, the general and mental status, life expectancy, nature and the origin of the pain, skin over the implantation area, patients environment and support systems should be considered.

Contra-indications: Include patient refusal, cachexia, sepsis and concomitant anticoagulant therapy.

Trial of spinally administered opioid:
Before implanting a drug, it is essential and a decision to implant should be made only after a positive trial response. Spinal opioid sensitivity should be tested to define the patient's probable acute response to spinal infusions and to suggest the out come likely to be anticipated from long term administration. The daily epidural /intrathecal opioid consumption, the level of activity and sleep, subjective pain scores, the need for additional analgesics and side effects should be recorded. During the trial time, systemically administered opioid medications are needed for break through pain. During the trial, the response to spinal opioid, the need for the addition of local anesthetics or other drugs, the administered route and the success of method can be assessed.

"Which Delivery System?"
In general, the delivery system is selected according to the life expectancy.

Temporary epidural catheter:
Percutaneous or subcutaneously tunneled epidural and intrathecal catheters are selected for patients with a short life expectancy, inactive patients for whom occasional dislodgement and replacement are preferable to implantation, or patients with severe pain for whom the short-term catheter immediately provides quick access and rapid relief, with further device planning at a future date.

Permanently implanted catheters:
If improved, pain control and decreased side-effects warrant more prolonged therapy, temporary catheters are, usually replaced by permanent implanted catheters within days to weeks. These systems have advantages in terms of sterility, comfort and freedom of movement for the patient. This requires either a port for percutaneous access or an implanted, pump- driven, percutaneously refillable reservoir system. The port system has a resealable membrane capable of withstanding percutaneous injections, and a filter to prevent particulate matter being injected spinally. There are various injection ports available port-a-cath, Spinalgesic, Spinoplast, Periplant, celsite and pharmacia epidural port. Disadvantages of such systems include numerous skin punctures, blockage of the port outlet or catheter, greater expense, the risk of infection and surgical intervention being needed for system placement or removal.

Implantable infusion device:
Indicated in patients with long life expectancy. They are initially expensive but have the advantage of low costs over time. The device is implanted with in the subcutaneous tissues of the anterior abdominal wall or subpectorally, the catheter being sited in the intrathecal or epidural space. The only significant drawback of such a system is usually the low reservoir volume.

Implanted pumps consist of a reservoir system and a pump mechanism. The pump mechanism can be driven either internally (by a lithium battery), externally (by an induction device) or mechanically (being patient operated). Pumps offering continuous plus-on-demand infusion rates are preferable to those with fixed infusion rates because of greater flexibility as 'Tolerance' develops.

Complications:
- Bleeding can occur at the surgical site - all anti-coagulants and NSAID's therapy should cease 3-7 days prior to implantation.
- Pump pocket seromas are self-limiting.
- CSF leakage may occur from accidental dural rupture during the epidural approach because of the discrepancy between size of the intrathecal catheter and that of needle.
- Post dural puncture headache - with persistent CSF leakage.
- A CSF Hygroma is mostly self-limiting with in 1-2 weeks.
- Infection can occur at catheter site, pump pocket, epidural space or intrathecal space.
- Needle placement and intrathecal catheter advancement can damage nerve roots, conus medullaris or the spinal cord itself, leading to radiculitis, myelitis, paralysis, paresis, loss of bowel and bladder control and/or myelopathic pain.

PCA is a relatively new route of drug administration, offering great promise in both pain control and research. Results from the management of chronic pain shows that PCA can lead to significant improvements in ambulatory patients with cancer. The fundamental principle of PCA is that it allows patients to reach their own analgesic state and thereby achieve an individual balance between pain relief and the appearance of side-effects.

The point at which the patient becomes uncomfortable enough to make a demand has become known as the minimum effective (blood drug) concentration (MEC). The MEC represents that concentration which removes the distress of pain but not necessarily the sensation of pain. When using PCA, patients should load themselves to exceed their MEC and then demand to deliver the drug as needed to maintain it. This demand pattern ensures that the patient maintains satisfactory pain relief without excessive sedation. Preoperative education concerning PCA may greatly influence its post-operative use.

A new transcranial electrostimulation device, the PULSATILLA, has now been developed for use in acute and chronic pain. Quasi-resonance produced by the pulses in the antinociceptive region of the brain induce accelerated ß-endorphin secretion. It consists of a microcontroller-based stimulus generator with resident medical soft ware library, and a head set with electrodes. One electrode is placed on the forehead and another on the mastoid bone behind each ear. The battery-operated generator emits pulses of a fixed and controlled frequency and shape at a maximum of 4mA strengths. Treatment sessions last up to 30 mins.

Contra-indications: Epilepsy, glaucoma, CNS disease, demand cardiac pace maker and skin damage over electrode areas.

Stereotactic radiofrequency (RF) procedures are a part of the range of nerve blocks available for relief of pain.

Principles: RF current traverses the tissues on its way from the electrode tip to the dispersive ground plate. This generates heat in the tissues around the electrode tip, where the current density is the highest. The rise in temperature in the tissues is transferred to the electrode tip, where a constant level of temperature is maintained by regulating the energy supplied from the lesion generator in response to changing electrical resistance in the tissues. In this way, charring of the tissues as occurs in electrocautery is prevented. The size of the lesion can be controlled, by monitoring the electrode tip temperature. It is also influenced by the vascularity of the surrounding tissue.

Advantages:
- Nerve destruction is localized, controlled in extent and reversible. Control of heat is also useful to limit destruction and minimize the risk of denervation dysaesthesia.
- The technique is minimally invasive.
- Accuracy of needle placement is facilitated by X ray monitoring.
- Most procedures can be accomplished under light sedation and local anesthesia.
- There is low incidence of complications.

Disadvantages:
- The RF equipment is expensive.
- Training and experience are required.

TENS is worth considering in patients with central pain who do not have severely reduced sensitivity for vibration and touch that is who have signs of fairly well preserved function in the dorsal column pathways. Thus, the proportion of responding patient is small and perhaps even smaller in the other central pain syndromes.

Principles that guide the use of complementary techniques in the management of chronic pain in children include:

- Recognition that education of children and their parents about the multi-dimensional nature of pain and its treatment is crucial to the success of complementary approaches. Without the understanding of the role that complementary treatments can play and the mechanism by which they may exert their effects, children and parents may refuse them, due to concern that health care providers do not see their pain as "real".

- A rehabilitative approach that emphasizes improving the child and families ability to cope with the chronic condition and decreasing pain related to emotional and behavioral conditions.

- The recognition that interventions need to be tailored to the child's individual characteristics not just to his/her specific conditions.

- An orientation toward prevention where possible by anticipating and aggressively managing acute pain, pain exacerbation and other stressors as they occur with in the context of a chronic pain condition.

Complementary techniques:

Acupuncture: Ancient Chinese medical technique involving stimulation of specific skin location by a variety of methods. Example: Needle insertion at acupuncture point.

Art therapy: Use of creative arts to modify pain and mood. Example: having children use arts and craft as a means to express feelings/concerns about their pain and its treatment.

Behavioral management: Use of operant and classical conditioning methods to manage pain-related disability. Examples: Rewarding a child's efforts to increase activities and comply with treatments; desensitizing a child to aversive aspects of medical treatment.

Breathing: Modulation of breathing to increase sensation of relaxation and exercises to distract the child from pain. Example: Deep breaths, "blowing away pain".

Biofeedback: Provision of auditory and/or visual feedback related changes in involuntary bodily responses to assist with the modification of these responses. Examples: Heart rate, galvanic skin response (GSR), hand temperature, and electromyography (EMG).

Cold therapy: Use of cold to provide local analgesia, typically for acute pain. Examples: Ice massage, vapocoolant sprays, cold packs.

Cognitive therapy: Modification of cognitions that exacerbate pain and mood. Examples: Reducing negative, "catastrophizing cognitions", increasing the child's positive self- statements about his/her abilities to cope.

Distractions: Use of any variety of methods that absorb the child's attention methods to reduce the child's focus on pain and pain treatment. Examples: bubble blowing, singing, videogames, party blowers, pinwheels.

Education: Providing age appropriate information to children about their pain, and the methods used to treat pain. Example: Explaining to a school age child that they can rub the injection site "close to the pain gate" before and after the shot.

Exercise: Prescribed activities to increase the child's functional capacities and reverse any pain related deconditioning. Examples: stretching, strengthening, flexibility, aerobic and range of motion exercises.

Heat Therapy: Use of heat to relieve muscle spasm, joint stiffness and increase local metabolism. Example: Hot packs, hydrotherapy, ultrasound.

Hypnosis: Induction of an altered state of consciousness, wherein the child is suggestible to alterations of sensation and perception. Examples: the child with CPRS may imagine herself turning off a pain switch to reduce sensation in an affected limb.

Massage and touch: Application of touch or force to soft tissues, usually without causing movement or change in joint position. Examples: Rubbing the site of a needle injection, stroking/ kneading sore muscles.

Mental Imagery: A multi-sensory representation of experience. Examples: Having children imagine themselves in a pleasant place doing some thing they really like to do, involving as many senses as possible in the image.

Music therapy: Use of music to modify mood and distract the child from pain. Examples: having the child sing a song or listen to favorite music.

Play therapy: Use of play to desensitize or educate a child about their plan and painful medical procedures. Examples: Play with medical props supervised by a play therapist or child specialist.

Relaxation: Techniques that reduce the stress response and produce feelings of mental calmness, usually involving a repetitive stimulus. Examples: Progressive muscle relaxation, meditation, autogenics.

TENS: Use of electrical stimulation that can be applied to the skin at different rates and intensities, to relieve pain. Examples: Positioning of TENS unit over muscle in spasm.


Pain Management Pain Management 03/30/2001
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