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Tramadol’s adverse effect profile is different from other opioids. The risk of respiratory
depression is significantly lower at equianalgesic doses (Tarkkila et al, 1997 Level II; Tarkkila et al,
1998 Level II; Mildh et al, 1999 Level II) and it does not depress the hypoxic ventilatory response
(Warren et al, 2000 Level II). Significant respiratory depression has only been described in
patients with severe renal failure, most likely due to accumulation of the metabolite M1
(Barnung et al, 1997).
In addition, tramadol has less effect on gastrointestinal (GI) motor function than morphine
(Wilder‐Smith, Hill, Osler et al, 1999 Level II; Wilder‐Smith, Hill, Wilkins et al, 1999 Level II; Lim & Schug,
2001 Level II). Nausea and vomiting are the most common adverse effects and occur at rates
similar to other opioids (Radbruch et al, 1996 Level IV). Tramadol given within recommended
dose limits does not increase the incidence of seizures compared with other analgesic agents
(Jick et al, 1998 Level III‐2; Gasse et al, 2000 Level III‐2).

4.1.3 Determinants of opioid dose
Interpatient opioid requirements vary greatly (Macintyre & Jarvis, 1996 Level IV) and opioid doses
therefore need to be titrated to suit each patient. Reasons for variation include patient age
and gender, genetic differences and psychological factors as well as opioid tolerance.
Patient age
Age, rather than patient weight, appears to be a better determinant of the amount of opioid
an adult is likely to require for effective management of acute pain. There is clinical and
experimental evidence of a two‐fold to four‐fold decrease in opioid requirements as patient CHAPTER 4
age increases (Burns et al, 1989 Level IV; Macintyre & Jarvis, 1996 Level IV; Gagliese et al, 2000
Level IV; Coulbault et al, 2006 Level IV; Gagliese et al, 2008 Level IV). The decrease in opioid
requirement is not associated with reports of increased pain (Burns et al, 1989 Level IV; Macintyre
& Jarvis, 1996 Level IV).
This age‐related decrease in opioid requirement is due mainly to differences in
pharmacodynamics or brain penetration rather than systemic pharmacokinetic factors (Scott &
Stanski, 1987; Minto et al, 1997; Macintyre & Upton, 2008) (see Section 11.2).
Gender

In general it has been found that females report more severe pain than males with similar
disease processes or in response to experimental pain stimuli (Hurley & Adams, 2008; Fillingim et
al, 2009). Response to opioids may also differ although both the degree and direction of
variation depend on many variables (Dahan, Kest et al, 2008). There is no consistent evidence for
any difference in mu‐opioid agonist requirements (Fillingim et al, 2009). However, kappa‐opioid
agonists such as nalbuphine and pentazocine have greater analgesic efficacy in women than in
men – see Section 1.6.2 .These variations as well as other known and unknown factors
involved in the very large interpatient differences in opioid requirements seen clinically, mean
that gender cannot be used as a basis for opioid dose alteration and confirms the need to
titrate doses to effect for each patient.
Acute postsurgical pain shows a tendency towards greater intensity in females, although the
evidence is inconsistent, as is the evidence for any difference in opioid requirements (Fillingim
et al, 2009). For example, higher pain scores and higher morphine requirements in the
immediate postoperative period have been reported for female patients (Cepeda &Carr, 2003
Level III‐2; Aubrun et al, 2005 Level III‐2). After knee ligament reconstruction, women reported
higher pain scores than men on the first day after surgery but there was no difference in
morphine consumption (Taenzer et al, 2000 Level III‐2). Females also reported more pain after
endoscopic inguinal hernia repair (Lau & Patil, 2004 Level III‐2), laparoscopic cholecystectomy (De

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