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Treatment of Pain Nyomtats E-mail

 

PALLIATIVE CARE AND PAIN TREATMENT   

EMBEY-ISZTIN DEZS, M.D.
JUDIT KISMARTON, M.D.
Budapest, 2002. 05.14.   

CONTENTS

Introduction..........................................
History and aim of „PALLIATIVE CARE” (Kismarton)......
Concept and evaluation of pain (Embey, Kismarton).....
Drugs used in the management of cancer pain Embey, Kismarton)....................................
     Minor analgesics (Embey).........................
     Mild opioids (Embey, Kismarton)..................
     Highly potent opioids (Embey, Kismarton).........
     Controlled release morphine tablet (Embey, Kismarton)...........
     Immediate release morphine tablet  (Embey, Kismarton)..............
     Intraspinal opioid administration (Embey)........
     Transdermal opioid / fentanyl administration     (Embey, Kismarton)...............................
     Continuous subcutaneous morphine administration     (Embey)..........................................
     Adjuvant analgesics (Embey, Kismarton)...........
     Alleviation of gastrointestinal symptoms of cancer    patients (Kismarton).............................
     Treatment of respiratory symptoms (Kismarton)....
     Treatment of mouth, skin and lymphoedema     (Kismarton)......................................

                    

INTRODUCTION


The goal of palliative medicine is to enhance the quality of life of cancer patients.    

Pain relief and „palliative care” of cancer patients can be considered to be one of the most important programs supported by the WHO. This is based on the fact that the incidence of cancer disease has been rapidly increasing all over the world. According to WHO data patients suffering from the 8 most frequently occuring cancer types will - without exception - require sooner or later symptomatic treatment. About 8O-9O % of malignant tumours occuring  in the developing countries can be considered practically incurable already at the time of diagnosis. Approximately 6 millions new cases have been annually diagnosed and more than 4 millions people die of the above disease. Taking into consideration the European data it has been found that 22 % of the annual mortality is due to cancer disease.

HISTORY AND AIM OF „PALLIATIVE CARE”


The „European Association of Palliative Care” has been founded in 1988 and from that time on has been making rapid progress all over the world.

The first steps towards „palliative care” were made in 1935. In that year were published the works by Alfred Worchester - „The Case of Aged”, „Dying” and „Death” -,  however, with no full success and appreciation. These publications were followed by similar ones  by the „Marie Curie Memorial Foundation” only 18 years later. Subsequently had been appearing the so-called „home care nurses”.

As a matter of fact, the history of palliative care began  essentially in 1967 when  St. Cristopher’s Hospice had been founded by Cicely Saunders in London. Recently many hospices have continuously been established all over the world. In the middle of the seventies in England - parallel with the rapid increase in the number  of hospices - the so-called „home care” has also come into being. This situation required the development of an appropriate nursing network which has begun to function in 1979 providing care for patients at home.
„Palliative care” is an active, complete symptomatic treatment - for the patient as well as for his/her family - performed by a multiprofessional team during the period  curative measures are judged ineffective.

Aim of „palliative care”: to provide the best possible quality of life for the patient and his/her family as well.

„Palliative care” has to be performed by a special team    of varying constitution, but - in order to work successfully - cooperation of patient,  family, friends, physicians and nurses is absolutely necessary. The best possible care - in both physical and psychological sense - can only be provided by team work.

The main principles of „palliative care” have been summarized by WHO in 199O as follows:

- helping life, respecting death as a natural process
- anticipation or prolongation of the time of death is
  is not allowed  
- alleviation of pain and other unpleasant somatic symptoms
- dealing with the psychic problems of the patient
- active and passive care should accompany the patient
  through his/her life
- helping family during the period of bereavement

„Palliative care” can be considered practically symptomatic therapy comprising of the following treatments:

- pain treatment
- alleviation of gastrointestinal symptoms
- treatment of respiratory problems
- treatment of mouth and skin
- care of urological problems
- treatment of occasionally developing lymphoedema
- neuropsychological care
     

CONCEPT AND EVALUATION OF PAIN


The definition of pain has been formulated by the „International Association for the Study of Pain” as follows:
„Pain is an unpleasant sensory or emotional experience resulting from an actual or potential tissue damage. Pain is always subjective. Everybody acquires the knowledge of using the word „pain” by itself, in consequence of injuries suffered in the infancy”.

For the better understanding of pain it can be useful to get acquainted with the „complete pain model” by Cicely Saunders. According to this model pain is made up  of the following factors:
          - physical
          - emotional/psychic
          - religious
          - social
These factors are closely correlated and this is considered also  the greatest challange of palliative care: „a special  symptom cannot be treated without taking into account all the other ones”.

Evaluation of pain:


Evaluation of pain is usually performed by the aid of  PQRST table.

P: Palliative factor: factors alleviating pain
   Provocative factor:factors provoking pain
Q: Quality:type of pain
R: Radiation:observed or not, if present, to which region
S: Severity:sharpness of pain
T: Temporal/continuous or intermittent pain

It is rather difficult to measure the intensity of pain because of the differences in the threshold of pain among individual patients. The „visual analogue scale” (VAS) can be conveniently  and easily used for the evaluation of pain. The simplest VAS contains 1O grades: O means total painlessness, 1O, however, unbearable pain. As a matter of course, many variations of VAS have been developed (e.g. the mood of the patient can also be evaluated in this manner).

Everyday use of questionnaires suitable for scientific elaboration (e.g. the Mc-Gill questionnaire) is rather difficult because they require much time and also have to be translated to the language of the individual country. Therefore in the practice much more simple and short questionnaires are used which are easy to fill in. Possibly „The brief pain inventory” (Visconsin USA) proved the best of them.

Classification of cancer pain


I. PAIN CAUSED BY CANCER (this is the most common,

   approximately 6O-7O %)
   -  bone pain
   -  neuropathic pain
   -  visceral pain

II. PAIN ASSOCIATED WITH CANCER THERAPY

    (approximately 2O-3O %)
    -  pain syndromes following surgical interventions
      (cutting of the intercostal nerve in the course
       of thoracotomy, damage of the cervical plexus
       during radical cervical block dissection,
       phantom pain following amputation, etc.) 
   -  pain caused by chemotherapy
      (e.g. polyneuropathy caused by treatment with vinca
      alcaloids)
   -  pain associated with radiotherapy
      (postirradiation brachial or lumbosacral plexus
      damage due to fibrosis, transverse myelitis,
      herpes zoster, etc.)

III. PAIN CAUSED BY GENERAL WEAKNESS

    - constipation
    - permanently bed-ridden patient

IV. OTHER TYPES OF PAIN

    - independent of the tumour
      (e.g. discopathy, spondylarthrosis, osteoporosis,
       etc.)
 

DRUGS USED IN THE MANAGEMENT OF CANCER PAIN


With regard to the fact that also patients suffering from metastatic cancer disease may be alive for months or sometimes even for years,  treatment of cancer pain have to be planned and performed by the physician for a long period of time. From among the recently available possibilities (drugs, nerve blockades, neuro-surgical interventions) the first method of choice should be the one causing the fewest side effects, but ameliorating pain satisfactory. More potent drugs  should be administered gradually in order to be able to alleviate even also  intracctable pain. The therapeutic plan constructed on the basis of the above conception is made known by the patient, simultaneously with thoroughly informing him/her about the possible side effects. Should we have whatever kind of effective drugs, our therapeutic efforts will only be successful if having gained the cooperation of our patients. This strategy postulates  that the patient should know everything about his/her illness and its current complications    (metastases, complications following treatments, side effects of drugs).
 
The treatment of cancer pain is primarily based upon drug administration. In approximately 7O % of cases cancer pain can be effectively ameliorated by using drugs and only 3O % of cases will require invasive interventions.

WHO proposals for adequate drug administration in case of cancer pain

- the drugs have to be orally administered,if possible
- the drugs must not be given occasionally or according
  to need, but on a regular, by the-clock basis
- the drugs must be given in adequate doses, taking
  into consideration the individual differences
  („alibi”  prescriptions should be avoided)
- in case of need adjuvant drugs have to be given 
- continuous monitoring of patients and regular
  modification of doses
- careful follow-up of patients, observation,
  prevention and treatment of side-effects.

The „three-stage analgesic scale”   by WHO helps to adequately treat cancer pain as follows:
 Step One
The first step of the analgesic ladder is to use a non-opioid analgesic. Adjuvant drugs to enhance analgesic efficacy .

Step Two
If the pain is persisting or worsening despite step one then a mild opioid should be added (not substituted). 

Step Three
When higher doses of opioid are necessary, the third step is used. At this step an opioid for moderate to severe pain is used, eg morphine fentanyl, hydromorphone, oxycodone, methadone etc. The dose of the stronger opioid can then be titrated upwards, according to the patient's pain as there is no ceiling dose for opioid.

Initial pain can usually can relieved by the so-called non-opioid or minor analgesics. As a matter of course, if preparations administered first have not proved to be sufficiently effective, therapy has to be switched to the use of mild opioids. If analgesia is still inadequate,  administration of highly potent opioids is recommended. Concomittantly with the prescription of mild or highly potent opioids previously administered minor analgesics should continuously be given in each case. Unfortunately, the everyday practice often does not meet the above guide-lines.


Analgesics can be classified as follows:

I.  Non-opioid analgesics or minor analgesics
    - non-steroid antiinflammatory drugs (NSAID)
    - aspirin
    - paracetamol
II. Weak opioid analgesics
    - codeine
    - dextropropoxyphene
    - dihydrocodeine
    - tramadol

III. Strong opioid analgesics (the most often used
     ones)
    - morphine
    - methadone
    - fentanyl
    - pethidine

I.Non-opioid (minor) analgesics


The most commonly used, mainly peripherally acting analgesics are NSADs and aspirin. If these drugs           - usually because of gastrointestinal side effects - are contraindicated, paracetamol should be given as drug of choice.

Aspirin:

In the clinical practice aspirin is considered to be the most commonly used salicylate preparation.
Absorption, metabolism: Aspirin is readily absorbed from the stomach and the small intestine. It is hydrolized by esterase enzimes present in the plasma, liver and other tissues. The plasma half-life of salicylic acid - the active metabolite - is 2-3 hours. Salicylic acid is  metabolized in the liver and excreted by the kidney.
Action: Anti-inflammatory, analgesic, antipyretic, platelet aggregation inhibitor. The anti-inflammatory and analgesic effects  are based upon the inhibition of the cyclooxygenase enzime and therefore on the decrease of the prostaglandin level.
Dose: The usual dose is 1O-15 mg/kg b.w.. The duration of the effect is approximately 3-4 hours, therefore the average dose for adults is 500-1000 mg in every 4 hours. Further increase in the dose will only intensify side effects, but will not increase analgesic  potency.
Contraindication: It should be carefully given to cachectic patients and those with hypoproteinaemia, severe liver- and renal failure, thrombocytopenia, coagulation disorders, gastritis and peptic ulcer. It is contraindicated for children under 12 years because of the risk of Reye’s syndrome.
Side effects: Lesion of the gastric mucosa, erosion, ulcer, bleeding, inhibition of platelet aggregation, prolongation of bleeding time, hypersensitivity (rhinorrhoea, laryngeal angioedema, bronchospasm, sensitivity, pruritus, urticaria, anaphylaxis), renal and liver lesion.
Drug interactions: Because of its strong binding to plasma proteins the effect of oral antidiabetics may be prolonged.
Overdosage: headache, tinnitus, dizziness, nausea, confusion, hyperventilation.

NSAIDs:

Their analgesic and anti-inflammatory effects are similar to those of aspirin, but because of having fewer gastrointestinal side effects NSAIDs are preferred to aspirin, especially slow-release preparations administered in every 12 or 24 hours.
Action: Anti-inflammatory, analgesic and antipyretic. In addition to the inhibition of prostaglandin synthesis, other effects on the central nervous system can also be supposed.
Side effects: Practically similar to those of aspirin. In case of confirmed hypersensitivity  to aspirin the administration of NSAIDs is also contraindicated. Relative contraindications: peptic ulcer, thrombocytopenia, haemorrhagic disorders, severe liver or renal failure. The most common gastrointestinal complications are as follows: erosion, ulcer, bleeding. If prolonged administration of NSAIDs will be necessary (multiple bone metastases), preventive measures  should be taken  (H2 receptor antagonists, proton-pump  inhibitors, prostaglandin analogues). Among side effects on the central nervous system headache, drowsiness, dizziness and - rarely occuring - psychosis have to be mentioned. Sodium and water retention, intestitial nephritis, tubular necrosis are considered the main renal side effects.
Practical use of NSAIDs in case of cancer patients:
In order to achieve a constant  analgesic effect long-acting slow-release preparations can be preferably administered two times a day (Voltaren 75 mg SR, Voltaren 1OO mg retard, Surgam 3OO mg) or once a day (Profenid 2OO mg).

Paracetamol:

In many countries it is considered the first drug of choice from among minor analgesics, because practically has no side effects.
Absorption, metabolism: It is absorbed mainly from the small intestine. Its plasma half-life is 2 hours. It is conjugated in the liver and excreted by the kidney. When high doses are administered the enzymatic metabolism in the liver may be insufficient and liver necrosis may develop.
Action: Analgesic, antipyretic effect, no anti-inflammatory action. Its effect is exerted presumably via the inhibition of prostaglandin in the central nervous system.
Dose: The usual dose for adults is 5OO-1OOO mg in every 4-6 hours orally or rectally.
Side effects: The usual therapeutic doses are well tolerated, rarely constipation, allergic skin rashes may occur. Long-term administration of 4-6 grams may lead to reversible increase in liver enzyme values.
Overdosage: May result in liver necrosis.
For oncological pain treatment can be very well combined with weak opioids (codeine or dextropropoxyphene: F.E.GENERIC NAME Solpadein, Panadein, Di-Antalvic).

II. Weak opioids


If minor analgesics alone can not sufficiently   ameliorate  pain, these preparations may be supplemented with the so-called weak opioids. Codeine, dihydrocodeine, tramadol and dextropropoxyphene (it is under registration  in Hungary) are the most commonly  used drugs of this type. From among weak opioids used for alleviating cancer pain slow-release dihydrocodeine tablet (DHC Continus) - acting on the basis of the controlled release principle - is the most frequently applied one.  At present it is available in tablets of 60 mg. The initial dose is 2 x 60 mg which can be increased maximally to 2 x 120 mg. Its side ffects are similar to those of morphine: initially nausea and vomiting, later constipation may occur. The 90 mg and 120 mg DHC Continus tablets are under development.
Tramadol: Capsules, suppositories, drops and injection are available. Its analgesic effect is 10times fewer than that of morphine. For alleviating cancer pain at least 400 mg has to be given, i.e. the recently available preparations have to be administered in every 4-6 hours. This is less comfortable  for patients than taking slow-release tablets.
Dextropropoxyphene: It is a synthetic methadone derivative. It can be well combined with paracetamol and in a short time will be marketed under the trade name Di-Antalvic.

III.Strong opioids (narcotic drugs)


For ameliorating torturing cancer pain highly potent opioids - also at present in most of the cases morphine - have to be given. Opioid analgesics exert their agonistic action by binding to various specific opioid receptors. For alleviating cancer pain pure agonists of  receptors are considered the most suitable  drugs. Among them morphine   - the most potent drug - is the preferred one, however, it is not equally potent in case of pain of various types. Especially neuropathic and bone pain can  not be adequately relieved by morphine alone. Practical use of this drug has been significantly improved by new routes of administration developed in the last 15 years. Formerly it was given usually intermittently subcutaneously or intramuscularly (unfortunately this is the case in many hospitals even also now), recently, however, good oral and rectal slow-release preparations are available and intraspinal and transdermal administration has also been developed.

MST CONTINUS tablet

As a result of the research work of late years concerning narcotic analgesics new preparations acting on the basis of the „controlled release system” principle have been manufactured. Drugs of the above type have to be swallowed as a whole - without chewing it -, independently of the fullness of stomach, that is the drug can be taken also before meals. Its absorption is also independent of the pH value in the stomach. The tablet absorbs steadily and reliably within about 8-1O hours, providing therefore a steady blood level for 12 hours. Its use is rather comfortable for the patient because it has to be administered in every 12 hours, and the dose taken in the evening guarantees a restful, painless night for the patient, therefore he/she does not have to get up neither because of pain, nor for taking analgesics. The special advantage of MST CONTINUS tablet - as compared to other preparations - consists in being usable reliably also rectally in a dose equal to the oral one.

DOSAGE:

The MST CONTINUS tablets are marketed in 1O, 3O, 6O and 1OO mg dosage forms.
The initial dose - apart from some exceptions - is for adult patients 3O mg in every 12 hours. The prescription of 2 x 1O mg as an initial dose is a rather often observed mistake, because this dose is undoubtedly inadequate  and will only discredit the preparation.
In case of aged patients or those with impaired renal function 2 x 2O mg or 2 x 1O mg may be indicated as an initial dose. Tolerance may, of course develop, but usually the upward titration of the dose will be necessitated by the progression of cancer disease.

The proposed scheme for dose escalation is as follows:
              2 x  3O mg
              2 x  6O mg
              2 x  9O mg
              2 x 12O mg
              2 x 18O mg
              2 x 24O mg
              2 x 3OO mg
              2 x 4OO mg
(Further on the dose has to be increased - every time if necessary - by 1OO mg.)   
It is evident from the above scheme that always the dose should be increased and the frequency of administration remains unchanged. (Very rarely taking the drug in every 8 hours can also be reasonable.)

If previously morphine was given to the patient in the form of injections.The daily oral or rectal dosage  has to be 3 times higher than the 24 hours injected one.
This is explained by the fact that due to first pass effect in the liver only 3O % of orally administered morphine dose will be biologically available. (E.g. if pain could be ameliorated by the administration of 12O mg injected morphine dose, the recommended dose of the slow-release preparation is 3 x 12O mg - that is 36O mg - in the course of 24 hours: 18O mg in the morning and 18O mg in the evening.)
If we would like to change from another opioid preparation over  MST CONTINUS tablets, the relative analgesic potency has to be taken into consideration according to the following scheme:

Previously used opioid preparation               Multiplying factor
morphine                                                      1
hydromorphone                                           4
methadone                                                   1.5
levorphanol                                                  7.5
meperidine                                                    0.01
oxycodone                                                   1

The usual dose of MST CONTINUS tablets in children is O.5-1 mg/kg b.w. in every 12 hours. In case of children it can somewhat more frequently occur than in case of adult patients that the drug has to be given - instead of 12 - in every 8 hours.

Side effects:

Tolerance, dependence, addiction, respiratory insufficiency may occur, but if MST CONTINUS tablets are prescribed in adequate doses and in case of real need, the above side effects will be very rarely observed. Two side effects may cause real problems: nausea/vomiting and constipation.

Nausea, vomiting:

The above side effects occur frequently  at the beginning of morphine therapy, and if we does not succeed in alleviating them, an alternative route of administration has to be applied.
Fortunately, tolerance develops within a relatively short time (1-2 weeks), therefore further on  this side effect will not cause problems. Metoclopramide and haloperidol are used most often as antiemetic drugs.
Constipation:
This is considered the most unpleasant and frequent side effect of long-term morphine therapy. Constipation is rather poorly tolerated by the patients who often discontinue taking this drug and are willing to tolerate pain rather than torturing obstipation. Preventive measures should therefore taken at the beginning of morphine therapy, and the development of obstinate constipation has to be prevented. Increased fluid intake, consumption of food rich in fibers, fruits and regular use of lactulose syrup and senna preparations is strongly recommended.

If also swallowing  of the small tablets makes is difficult for the patient, or enteral tube alimentation has to be used, controlled release morphin  granulate / MST CONTINUS SUSPENSION / is  recommended.This preparation will  be marketed in sachets with  1O mg, 3O mg, 6O mg, 1OO mg and 2OO mg. The dosage is twice daily .These preparations have to be dissolved in water immediately before use. The  suspension has a raspberry taste.
If the administration of the drug into the stomach is unsuccessful through  the tube, reliable manufactured suppositories can also be used (they are under registration), but it has to be remarked again that MST CONTINUS tablets can be applied in equianalgesic doses also rectally or at any other mucosa as well..

Sevredol (immediate release morphine)

It is unquestionable that in case long-term oral morphine therapy has to be applied, use of slow-release preparations (MSA CONTINUS tablets) is the most comfortable treatment for the patients. In possession of the appropriate practical knowledge also dose titration can  be carried out immediately with the slow-release preparations (MST CONTINUS tablets). However, titration of the initial dose  - which takes  usually 2-3 days -, can be facilitated by using immediate release morphine tablets which will be soon marketed also in Hungary as SEVREDOL 1O mg and 2O mg tablets. The use of immediate release morphine tablets (SEVREDOL) is even more important for the treatment of the so-called break-through pain provoked usually by movements. The following table summarizes the doses of the immediate release morphine tablets (SEVREDOL) compared to the respective MST CONTINUS doses.

Dose of MST CONTINUS tablets (mg) given in every 12 hours     Dose of SEVREDOL tablets ( mg)
30                                                                                                                            10
60                                                                                                                            20
120                                                                                                                          30
180                                                                                                                          60
240                                                                                                                          80
300                                                                                                                        100
400                                                                                                                        130
500                                                                                                                        150
600                                                                                                                        200

If the administration of immediate release morphine tablets (SEVREDOL) becomes necessary regularly more than two times a day because of break-through pain, increasing the dose of the slow-release morphine tablets (MST CONTINUS) can be considered reasonable.
Using immediate release morphine tablets (SEVREDOL) makes the (subcutaneous or intramuscular) injection of morphine preparations causeless.

Intraspinal opioid administration:

The main point of the intraspinal administration is that small doses of an opiate (usually morphine) are injected epidurally or intrathecally  through a catheter inserted into the spinal canal.
Its advantage consists of attaining excellent analgesic effect without causing vegetative or motor blockade, even also by using small doses. As a disadvantage, however, has to be mentioned that insertion of the catheter is considered to be an invasive procedure which - although rarely - can lead to serious complications (epidural abscess, meningitis). In order to prevent complications special, completely implantable systems and for providing steady dosing of the drugs external and implantable pumps have been developed. The use of very expensive, completely implantable pumps for a 1-2 months intraspinal morphine treatment is, however, questionable. On the other hand, marketing of modern slow-release tablets (MST CONTINUS) has significantly decreased the necessity of intraspinal morphine administration.

As an example for the above arguments  the statistics of the Department of Analgesia  of the National Institute of Oncologogy can be mentioned which unequivocally  show how  the marketing of MST CONTINUS tablets since 1994 has changed the previous practice of drug administration.

Transdermal opioid administration:

When morphine can not be used because of continuous vomiting or inability of swallowing, transdermal opioid administration can be an excellent, new possibility. Transdermally fentanyl - a synthetic narcotic analgesic 1OO times stronger than morphine - can be applied. Transdermal patches are marketed in 4 different dosage forms which provide the transdermal absorption of 25, 5O, 75 and 1OO g active agent in an hour. The patches have to be changed in every 72 hour. If higher amounts of opioids become necessary, several  patches can be used at the same time. The therapeutic blood concentration develops slowly, therefore immediate release opioids may be necessary (SEVREDOL tablets) on the first day. On the other hand, after having removed the patch some absorption will occur for one more day from the subcutaneuous reservoir.
The following table shows the transdermal fentanyl doses compared to the 24 hours oral morphine sulphate doses.

Oral morphine sulphate

 mg/24 hours     transdermalis fentanyl mikrog/Hours
                    -  135                      25
                135-224                      5o
                225-314                      75
                314-4o4                    1oo

(Based on the proposal of the Janssen documentation)     

Continuous subcutaneous morphine administration

If the above mentioned routes of morphine administration can not be applied for any reason and when the patient is in the final stage of cancer disease, excellent analgesic effect can be attained by continuous subcutaneous morphine administration. A  scalp vein set  inserted subcutaneously into the skin of the abdomen or chest has to be connected to a portable injection pump (e.g. Braun-Rolitron type)  hereby providing  the continuous administration of the drug around the clock. Due to the steady blood level, continuous analgesic effect will be attained with relatively few sedative side effects. Continuous subcutaneous morphine administration is considered especially important in palliative care units and in home care. As a special advantage can also be mentioned that - mainly in case of patients in the final stage of cancer disease - not only analgesics, but also sedatives and antiemetics can be  given at the same time by this route of administration.

Adjuvant analgesics:

It has already been mentioned that by the administration of analgesics alone cancer pain can not be sufficiently treated , because for example neuropathic pain or that caused by multiple bone metastases can not even be relieved by the administration of morphine in itself. In these cases prescription of adjuvant analgesics is absolutely indicated.
Pharmacologically adjuvant analgesics can not be regarded as real analgesics, but in some  cases they may be more potent in intractable  pain than real analgesics.

Classification of adjuvant analgesics:

1. drugs used in multiple indications
2. drugs used in case of neuropatic pain
3. drugs used in case of bone pain


Ad 1.
Drugs used for multiple indications
- corticosteroids
- neuroleptics
- antihistamines
- benzodiazepines

In this group corticosteroids are the most important analgesic drugs in the following cases:

- raised intracranial pressure
-acut spinal cord compression 
-neuropathic pain  due to infiltration or compression by tumor
-hepatic capsular distension
-metastatic bone pain

Ad 2.
Drugs used for alleviating neuropathic pain
Neuropathic pain is one of the most hardly relievable  symptom caused by central or peripheral nerve lesion. The characteristics of this type of pain differ from the well localized and acute nociceptive pain.
The characteristics of neuropathic pain are as follows:
One of its components is an intermittent, aching pain, similar to electric shock which is often accompanied by a spontaneous burning sensation together with allodynia and hyperaesthesia.
For ameliorating neuropatic pain the following two drugs can be used:
a) carbamazepine
b) amitriptyline

Carbamazepine can be used primarily for alleviating aching, neuralgia-like pain, amitriptyline, however, for ameliorating burning pain, allodynia and hyperaesthesia.
Amitriptyline - by inhibiting the reuptake of norepi-nephrine and serotonin increases the central level of these monoamines, therefore the descending pathway - inhibiting conduction of pain - will be activated. It has a special practical significance that the advantageous action of amitriptyline is achieved in about 7-1O days, therefore patients have to be warned not to stop arbitrarily taking this potent drug because of the earlier developing anticholinergic side effects (dryness of the mouth, difficulties in urination).

Ad 3.
Drugs used in case of bone pain
Bone tumours are much more frequently metastatic than primary processes. Usually breast, prostate, bronchial, thyroid  and renal cancers are accompanied by bone metastases. In case of bone pain traditional analgesics can not sufficiently alleviate especially movement related pain..

Drugs indicated for ameliorating bone pain:

- aspirin and NSAIDs
- steroids
- biphosphonates
- calcitonin
- radioisotopes

When treating bone pain the most often occuring mistake consists of disregarding peripheral analgesics and prescribing opioid analgesics (pethidine tablets) in mono-
therapy. In case of bone pain aspirin or NSAIDs are the first drugs of choice. As a matter of course, narcotic analgesics can also be used, if necessary. With regard to the fact that NSAIDs have to be administered for several months, it is rather important to try to prevent and treat gastrointestinal side effects with the following drugs: H2 receptor antagonists (ranitidine, famotidine), proton-pump inhibitors (omeprazole) and prostaglandin E analogues
(misoprostol).

Biphosphonates inhibit osteoclastic  activity and thereby  decrease osteolysis. In therapeutical use they are indicated in intravenous or oral dosage form  for moderating hypercalcaemia and for analgesia.


Calcitonin decreases osteoclastic activity by binding to the osteoclastic receptors.

Radioisotopes

The use of radionuclides is indicated especially for ameliorating pain elicited by multiple bone metastases in prostate and breast cancer. They are administered as iv. injections. One treatment may result in a several months alleviation of pain. Carefull haematological monitoring is necessary.

Alleviation of gastrointestinal symptoms of cancer patients

The most frequently occuring gastrointestinal symptoms are vomiting and nausea.
The vomiting center found in the medulla oblongata contains histamine and muscarinic cholinergic receptors. The vomiting center can be activated by several ways. Some drugs (e.g. the opioids) stimulate directly the chemotactic trigger zone  of the area postrema where high numbers of dopaminergic receptors are found. Increase in the intracranial pressure directly stimulates the vomiting center. The activation may also occur via the vagal nerve and the vestibular system.

The most common reasons of vomiting are as follows:

     - direct effect of primary or metastatic cancer
     - drug effect
     - uraemia
     - constipation
     -raised intracranial pressure
     - psychic disorders
First it has to be tried  to cease the basic reason  of vomiting. This often proves to be unsuccessful, but it is important to  provide a pleasant sensation for the patient. In such a case, of course,  symptomatic treatment has to be performed.

The most often used antiemetic drugs


Name of  the active agent         daily dose 
       / mg /
cyclizin                                        1oo-2oo
domperidon                                 1.5-15
metoclopramid                            3o-1oo
ondansetron                                    8
haloperidol                                     1.5-15


Steroids are very effective in potentiating the action of ther antiemetic drugs and in decreasing the oedema of tissues around the tumour. Steroids play an important role in decreasing cerebral oedema and also in increasing the appetite of the patient.   
Constipation is also a rather common complication which is usually caused by the administration of opioid analgesics.

Other reasons of constipation:

     - direct effect of primary or metastatic cancer
     - prolonged hospitalisation
     - general weakness
     - insufficient food intake, lack of appetite

Possibilities for the ciasing of constipation:

     - intake of food of high fiber content
     - prescription of laxatives (lactulose, senna, etc.)
     - high fluid intake
     - rectal oily enema

The problem of diarrhoea occurs much rarely. It is usually caused by malabsorption following surgery or by drug administration. 1O-15 mg of  codeine can be successfully used to treat diarrhoea.  In case it seems to be uncontrollable,     imodium should be administered.
Dysphagia and intestinal obstruction may be observed as rare complications. Dysphagia may occur mainly in case of patients underwent surgery because of cervical cancer. According to our experiences dysphagia is usually caused by pain, therefore by alleviating pain also this problem will often be solved.

In inoperable  cases of intestinal obstruction symptomatic therapy is essential. For treating uncontrollable vomiting in such a case   Somatostatin (Octreoid) can be success-fully administered, because it decreases intestinal secretion and therefore vomiting. The usual daily dose is O.1-O.6 mg/day. It is indicated mainly in cases when other conservative treatments are ineffective.
Because of the fact that in most of the cases of various gastrointestinal complications only parenteral drug administration can be performed, it is important to mention the possibility of using a pump providing continuous subcutaneous administration. Through a scalp vein set inserted subcutaneously into the the skin of the abdomen the respective drugs can be continuously administered by the aid of the pump. The pump is portable, therefore the patient does not have to lie in bed permanently.

Treatment of respiratory symptoms

 

The most often occuring respiratory problems are cough and dyspnoea. Dyspnoea is a difficult and  exhausting respiration observed in most of the patients in the final stage of the disease. It is very unpleasant for the patient and often causes fear of death.

The most common reasons of dyspnoea are as follows:

        -  cardiovascular
        -  respiratory
        -  gastrointestinal
        -  metabolic
The therapy applied in such cases  is similar to that given usually in the general practice. Steroids ameliorate bronchospasm and pulmonary oedema, atropine decreases bronchial secretion and has a bronchodilator effect as well. Benzodiazepines and opioids have  to be mentioned as well. If necessary, oxygen therapy can also be applied. In case dyspnoea is caused by pneumonia, administration of antibiotics is also necessary.
The other important respiratory symptom is cough. It can be caused either by mechanical irritation of tracheal or bronchial receptors or by chemical irritation of acini. Its treatment is similar to that of dyspnoea, but - if needed -
mucolytics (N-acetyl-cysteine) and expectorants have to be given as well.

Treatment of mouth, skin and lymphoedema


In order to attain good oral hygiene,  dental creams have to be used. In certain cases the tongue is coated to such an extent that the use of dental creams is not enough.  In such cases rinsing is indicated  with sodium-hydrocarbonate or vitamin C-containing solution. In case of patients treated with cytostatic drugs or steroids mycotic  infection of the mouth is rather common. In such cases metronidazole up to a dose of 4OO mg/day has been found the most effective drug. If the tongue or the mouth is painful- because of ulceration caused by the infection -rinsing with camomile or a local anaesthetic can be performed. (Administration of steroids is contraindicated because of the risk of superinfections.)
Therapy of the skin aims at treating infections and its consequences: necrosis, bleeding and pain which are very important to be prevented primarily by the aid of hygienic measures and by avoiding compression. In case of infection local metronidazole treatment has to be applied, following, of course, local antiseptic therapy.

The therapy of lymphoedema is much more difficult. High doses of steroids and special lymphoedema treatment         - taught at special lymphoedema clinics - can be very useful. This consists of a massage and a specially applied bandage. However, the effect of the above treatment often proves to be only temporary.

Home care


Nowadays home care has become more and more common.
In 1993 the significance of „home care” has been emphasized in England as a further aim  of „palliative care”.
Aim: Complete care of patients in natural environment that is in their own home, within the range of possibility.
Proper „home care” involves the participation of the whole family, because the therapeutic strategy has to be made acquainted with them. It is rather important to inform them about the effects and side effects of the drugs administered. They have to be given practical advices and prepared for all the possible  consequences.
The „home care” team consists of the following persons: physicians, nurses, social workers, psychotherapeutics, chaplains and medicinal gymnasts.
The team performing home care has to be in close connections with the family doctor of the patient. In many cases it is the family doctor - in some cases, however, the hospital - who asks „home care” physician to pay the first visit at the patient. This time drug therapy and eventually also medicinal gymnastics have to be decided. Initial treatment has to be  performed by the physician, continuous control, however, by „home care” nurses. The frequency of their visits is highly influenced by the condition of the patient. Nurses should pay at least weekly visits at the patients’  home, control their general condition and - if necessary - also slightly modify drug therapy, with the exception of narcotic analgesics. The dose of the above drugs can be changed after having it discussed with the physician on the telephone. It also falls under the tasks of the nurse to apply for medical consultation, if necessary. The physician - depending  on the condition of the patient - may modify the therapy or may send the patient to the hospital for further treatment.
The role of psychotherapeutists and social workers can not be overemphasized. Patients in the final stage of the disease are usually depressed. In such cases psychotherapy is often more important than drug administration. Patients in the terminal stage often have fear of death, fear of losing family, friends and hope. The psychic condition of patients is rather understandable, because adherence to life is an important part of the basic instinct.

                   




            
  
       


             
                                                                       
            

 
 
 
 
   
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