Opioid receptors are currently classified as mu (mu: mOP), delta (delta: dOP), 
kappa (kappa: kOP) with a fourth related non-classical opioid receptor for 
nociceptin/orphainin FQ, NOP. Morphine is the current gold standard analgesic 
acting at MOP receptors but produces a range of variably troublesome 
side-effects, in particular tolerance. There is now good laboratory evidence to 
suggest that blocking DOP while activating MOP produces analgesia (or 
antinociception) without the development of tolerance. Simultaneous targeting of 
MOP and DOP can be accomplished by: (i) co-administering two selective drugs, 
(ii) administering one non-selective drug, or (iii) designing a single drug that 
specifically targets both receptors; a bivalent ligand. Bivalent ligands 
generally contain two active centres or pharmacophores that are variably 
separated by a chemical spacer and there are several interesting examples in the 
literature. For example linking the MOP agonist oxymorphone to the DOP 
antagonist naltrindole produces a MOP/DOP bivalent ligand that should produce 
analgesia with reduced tolerance. The type of response/selectivity produced 
depends on the pharmacophore combination (e.g. oxymorphone and naltrindole as 
above) and the space between them. Production and evaluation of bivalent ligands 
is an emerging field in drug design and for anaesthesia, analgesics that are 
designed not to be highly selective morphine-like (MOP) ligands represents a new 
avenue for the production of useful drugs for chronic (and in particular cancer) 
pain.