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Morphine is one of the most commonly used painkillers in cancer patients. Unfortunately, the myths about opioids that have survived over the years, often make effective analgesia difficult to achieve .
Aim: The aim of our work was to evaluate the effect of morphine on the cognitive function of cancer patients, taking into account the effect of the clinical status and dose of the drug.
Materials and Methods: The computerized CDR (cognitive drug research) system and paper tests were used for the study. Patients with hepatic and renal insufficiency and patients receiving corticosteroids are excluded from the study. We examined patients: in advanced stage of cancer with good mental performance determined by the Minimental State scale untreated with strong opioids, papaverine, codeine, corticosteroids in the last 4 weeks preceding the study. We’ve examined 68 patients, 40 patients have completed the study.
Results & conclusions: In the morphine-treated group, the speed of attention (selection response time), quality and speed of long-term memory (word memory) deteriorated, and the quality of memory (spatial memory and number memory) decreased. Statistical inference proved that the dominant factor affecting cognitive functions is the general state of the patients.
Pain is an inevitable sign of cancer. According to the WHO guidelines, opioids are the basic treatment of moderate to severe pain. Despite the lack of strong scientific evidence, opioids are attributed a series of negative effects on the psyche and cognitive abilities of man. This results in fear of opioid use, especially morphine. The most famous fact about morphine is that it is addictive . The second well-known fact is that morphine causes respiratory depression . Despite the lack of evidence showing that morphine has a negative effect on mental performance, in many countries its taking results in the inability to take legal action, to operate machines and to drive vehicles .
Morphine myths, which have survived for years, often hinder effective analgesia . The decisions made by patients taking opioids are questioned and their validity is questioned in the context of legal action. Many patients at the end of their lives receive strong analgesia, while at the same time making important life decisions, such as writing down a will. The results of previous studies on the influence of morphine on cognitive functions are not clear. Studies are usually conducted on small
groups of patients or on healthy volunteers, using a variety of not always complementary research tools. It is known that not only drugs but also a pain shape the cognitive ability of man. It is more appropriate to evaluate the effects of analgesics in sick people than in healthy people . Although cancer patients are the largest group using opioid analgesics, there are only a single study of them. The reason is probably the research difficulties of this particular group of patients.
The main objective of this research is a detailed assessment of the effect of morphine on the cognitive function of patients, taking into account the influence of socio-demographic factors, general condition of patients and dose of the drug.
a) After inclusion morpine according to standards of
analgesic treatment, we assess the efficacy of analgesia with VAS
scale for consecutive days after inclusion. The patient was reexamined
with paper tests and a computerized CDR test on the
third day after achieving analgesic effect (VAS up to 2).
b) Cognitive Evaluation - CDR-P Cognitive Drug Research
Program Automated cognitive assessment tests are a recognized
way of assessing cognitive ability. In numerous studies of the
effects of drugs are more sensitive compared to paper tests.
Collected data is saved in Excel spreadsheet. The obtained
results were subjected to statistical analysis using statistical
computer package STATISTICA PL v.8. Statistical description of
the variables was made with calculating mean value (arithmetic
mean) and standard deviation. Quality data was presented in the
form of frequency and interest tables. The statistical inference
for verifying the hypothesis of mean equality was performed on
the basis of the Student’s t test, after checking the conditions of
application of the parametric tests. The relationships between the
variables studied were estimated R-Pearson’s product moment correlation coefficient. All hypotheses for the null hypothesis
criteria were assumed to be p <0.05 .
After achieving the therapeutic effect by morphine statistically
significant changes in the quality and speed of all areas of
cognitive function were noted (attention, memory and long-term
memory). Morphine-treated patients performed worse than
before treatment. Mainly memory-related processes have been
impaired. Taking the drug was correlated with less accuracy and
sensitivity in terms of spatial working memory (SPMOACCI and
SPMSI tests), less accurate identification of numbers. There was
a negative impact of the drug on the quality and the long-term
memory speed, patients slower and less accurately recognize
the presented words (DRECOAC and DRECSI test). In addition,
attention-related processes (CRTs) were released (Figure 1&2).
There was a correlation between the size of cognitive
improvement and the time needed to achieve the pain effect.
Cognitive changes in patients with short-term pain treatment
(less than 4 days) are much faster.
In patients treated with morphine over 10 days there’s no
or just little cognitive improvement. This concerns two aspects of word recognition. Namely, in a group with a faster therapeutic
effect, the rate of improvement in the rate of speech recognition is
higher than in those treated for longer.
The same relationship also applies to the overall rate of word
recognition. Simple response time improves in patients treated
shortly but worsens in patients treated over 10 days.
There was no statistically significant relationship between
dose and cognitive performance. Morphine treated patients
received from 10 to 120 mg orally or in subcutaneous injections.
To objectify the answer to the above-mentioned thesis, the criteria
for qualifying patients for the study were rigorously observed.
Exclusion of the patients with renal and hepatic failure has
eliminated the factor that increases blood and urine drug levels.
The exclusion of papaverine and codeine reduced the errors
in biochemical determination of concentration of drugs and their
metabolites in the blood. The ban on steroid use was linked to the
fact that these drugs could affect cognitive decline .
The coefficients of correlation between ECOG values on
the one hand and cognitive measurements on the other were
calculated. The results indicate that the cognitive functioning of
the patients studied remains correlated with their general state.
This relationship is statistically significant for many variables, but
the correlation values are not large. These statistically significant
relationships occurred in all major areas of cognitive function,
namely attention, memory and long-term memory. Patients with
poorer general condition of attention quality have made more
mistakes in detecting stimuli (changing numbers) and their
reaction time has increased. Patients in the worse general state
exhibited significantly longer response times to the presented
stimuli - word recognition in the original and new stimulation
variant, and longer response time to the stimulus in the form
of digits. Long-term memory was also found in the presence of
statistically significant relationships between the general state
and the cognitive functions of the group. Patients in worse general
condition were less likely to recognize words and images after the
postponement of time and the performance of these tasks took
place in extended time.
In our study, we thoroughly evaluated the effect of morphine
on patients’ cognitive function. Analysis showed that after
morphine consumption, statistically significant deterioration has
changed for all major areas of cognitive decline. Morphine has slow
down processes and long-term memory and has compromised
memory performance and long-term memory. What’s essential
- we indicate that the cognitive functioning of patients remains
correlated with their general state. We’ve used computer tests
because of their superiority over paper tests.
Wesnes, in rivastigmine studies , and Walker in interleukin
2 studies [11,12] have demonstrated that the results of automated
tests are more sensitive to drug-induced changes. The advantage
of automated testing over traditional methods has also been
demonstrated in previous observations by Corani  and Brook
 on morphine.
For a thorough analysis of the problem, 68 patients were
examined and the study was completed by 40 people. These data
support the fact that patients with advanced cancer are a difficult
research group, and their eligibility for clinical trials is difficult.
Severe general condition of patients often makes it impossible to
carry out time-consuming research and testing. For example, the first stage of study (VAS scale, socio-demographic history, CDR)
performed a total of 45 to 90 minutes. Definitely better general
condition of the patients facilitated the conduct of the study and
increased the chances of completing the second stage of the study.
This is probably due to the relatively short predicted survival
time of the patients studied. In addition, the available literature
provides, as a rule, the following:
a) Groups of small numbers. Probably a small number
of the examined groups is caused by reasons mentioned above.
Available studies typically involve over a dozen people [15-18].
Difficulty in completing the research group is also due to the
fact that patients with advanced cancer are undergoing other
medical conditions, often using pharmacotherapy that disqualifies
them from the study.
b) The reason for doing the above research were no clear
data of the effect of morphine on the cognitive functions of
patients with advanced cancer.
Although numerous publications on morphine
pharmacokinetics are available, these are only single observations
for patients with advanced cancer. The available literature refers
very ambiguously to this problem.
Long-term follow-up of Tassain’s results, indicates that
morphine therapy does not impair cognitive ability and even
improves it to a small extent . However, taking long-term
study time (up to 12 months), it can be assumed that the patients
observed by Tassain were in significantly better clinical conditions
than the patients tested by us. Against Tassain’s research, the
results of Sjogren’s analysis , which evaluated non-cancer
patients receiving chronic morphine for pain. 40 patients were
treated with regular, regular doses of morphine. Cognitive tests
used continuous reaction time (CRT) tests, which evaluated the
FTT (finger tapping test), a psychomotor test; And PASAT (paced
auditing serial addition task), which evaluates working memory.
The results showed that patients performed tests worse than
the control group of volunteers. This test confirms our results,
especially since it uses similar neuropsychological tests. Wood has
examined hospice patients with equivalent research tools as we
. The results of his analysis did not show memory impairment,
but the quality of attention and the ability to process information
were impaired. Similarly to our observation, long-term memory
Vainio evaluated the long-term effects of controlled-release
morphine on cancer patients cognitive and psychomotor
functions. He used neurological, psychological and special tests
for drivers. The results were compared with those in the control
group (cancer patients without pain). There were no statistically
significant differences between the groups in terms of vigilance,
attention and liquidity in performing psychomotor tasks. The
results of the tests in “morphine” patients were slightly worse
than in the control group .
In contrast to our observations, Morita’s findings show that
confusion occurs at the start of opioid treatment and disappear
after about one week of use [2,17,22]. Wood and Morita are the
only researchers of opioid treatment in the late stages of life
[15,17]. Their value raises the fact that they evaluate by specific
psychological tests variables such as short-term memory and longterm
concentration. These tests showed a lower level of intellectual
function than the mean, although there was no impairment in
clinical judgment. Wood et al.  used psychological tests to
examine hospice patients during morphine treatment. They did
not find fresh memory disturbances in them, but attention was
concentrated and the ability to process information. The longterm
memory was also significantly impaired. In this study no
relationship was observed between the route of administration
(p.o. and s.c.), dose and concentration of morphine metabolites
and cognitive impairment . Similar memory disturbances
have been reported by Cull in his study of patients with remitting
lymphoma . It was found that when using morphine at
doses prescribed by the patient as being sufficient to control
pain, cognitive impairments caused by somnolence were not
observed. Cognitive improvement after pain relief is most likely to
compensate for morphine drowsiness  and cognitive function
is more impaired by pain than morphine.
Verifying the research on the effect of opioids on cognitive
function and getting answers to the question of how they affect
cognitive performance is difficult. In the morphine-treated group,
the speed of attention (selection response time), quality and
speed of long-term memory (word memory) deteriorated, and
the quality of memory (spatial memory and number memory)
decreased. Negative importance of morphine seems to be
overestimated. statistical inference points that dominant factor
affecting cognitive function is the general condition of the patient.